Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent

ABSTRACT

Disclosed in certain embodiments is an oral dosage form comprising a therapeutically effective amount of an opioid analgesic; an opioid antagonist; and a bittering agent in an effective amount to impart a bitter taste to an abuser upon administration of the dosage form after tampering.

[0001] This application claims the benefit of U.S. Provisional SerialNo. 60/310,513, filed Aug. 6, 2001, hereby incorporated by reference inits entirety.

BACKGROUND OF THE INVENTION

[0002] Opioid analgesics are sometimes the subject of abuse. Typically,a particular dose of an opioid analgesic is more potent whenadministered parenterally as compared to the same dose administeredorally. Therefore, one popular mode of abuse of oral opioid formulationsinvolves the extraction of the opioid from the dosage form, and thesubsequent injection of the opioid (using any “suitable” vehicle forinjection) in order to achieve a “high.”

[0003] In the prior art, there have previously been attempts to controlthe abuse potential associated with opioid analgesics. For example, thecombination of immediate release pentazocine and naloxone has beenutilized in tablets available in the United States, commerciallyavailable as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx is indicated forthe relief of moderate to severe pain. Talwin®Nx contains immediaterelease pentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. The amount of naloxone presentin this combination has low activity when taken orally, and minimallyinterferes with the pharmacologic action of pentazocine. However, thisamount of naloxone given parenterally has profound antagonistic actionto narcotic analgesics. Thus, the inclusion of naloxone is intended tocurb a form of misuse of oral pentazocine which occurs when the dosageform is solubilized and injected. Therefore, this dosage has lowerpotential for parenteral misuse than previous oral pentazocineformulations.

[0004] A fixed combination therapy comprising tilidine (50 mg) andnaloxone (4 mg) has been available in Germany for the management ofsevere pain since 1978 (Valoron®N, Goedecke). The rationale for thecombination of these drugs is effective pain relief and the preventionof tilidine addiction through naloxone-induced antagonisms at themorphine receptor. A fixed combination of buprenorphine and naloxone wasintroduced in 1991 in New Zealand (Temgesic®Nx, Reckitt & Colman) forthe treatment of pain.

[0005] Purdue Pharma L. P currently markets sustained-release oxycodonein dosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochlorideunder the tradename OxyContin.

[0006] U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,295disclose sustained release oxycodone formulations.

[0007] U.S. Pat. No. 4,769,372 and 4,785,000 to Kreek describe methodsof treating patients suffering from chronic pain or chronic coughwithout provoking intestinal dysmotility by administering 1 to 2 dosageunits comprising from about 1.5 to about 100 mg of opioid analgesic orantitussive and from about 1 to about 18 mg of an opioid antagonisthaving little to no systemic antagonist activity when administeredorally, from 1 to 5 times daily.

[0008] U.S. Pat. No. 6,228,863 to Palermo et al. describes compositionsand methods of preventing abuse of opioid dosage forms.

[0009] WO 99/32119 to Kaiko et al. describes compositions and methods ofpreventing abuse of opioid dosage forms.

[0010] U.S. Pat. No. 5,472,943 to Crain et al. describes methods ofenhancing the analgesic potency of bimodally acting opioid agonists byadministering the agonist with an opioid antagonist.

[0011] Additionally, Shaw et al., U.S. Pat. No. 3,980,766, relates todrugs which are suitable for therapy in the treatment of narcotic drugaddiction by oral use, e.g., methadone, formulated to prevent injectionabuse through concentration of the active component in aqueous solutionby incorporating in a solid dosage or tablet form of such drug aningestible solid having thickening properties which cause rapid increasein viscosity upon concentration of an aqueous solution thereof.

[0012] However, there still exists a need for a safe and effectivetreatment of pain with opioid analgesic dosage forms which are lesssubject to abuse than current therapies.

[0013] All documents cited herein, including the foregoing, areincorporated by reference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0014] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless parenteral abuse than other dosage forms.

[0015] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless intranasal abuse than other dosage forms.

[0016] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless oral abuse than other dosage forms.

[0017] It is a further object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless diversion than other dosage forms.

[0018] It is a further object of certain embodiments of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid analgesic while reducing the abuse potential of thedosage form.

[0019] It is a further object of certain embodiments of the invention toprovide a method of manufacturing an oral dosage form of an opioidanalgesic such that it has less abuse potential.

[0020] These objects and others are achieved by the present invention,which is directed in part to an oral dosage form comprising an opioidanalgesic; an opioid antagonist; and at least one aversive agent forreducing the abuse of the opioid analgesic.

[0021] In certain embodiments of the present invention, the oral dosageforms of the present invention comprising an opioid analgesic; an opioidantagonist; and an aversive agent or agents as a component(s) of thedosage form helps to prevent injection abuse by decreasing the“attractiveness” of the dosage form to a potential abuser.

[0022] In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a bittering agent to discourage anabuser from tampering with the dosage form and thereafter inhaling orswallowing the tampered dosage form. Preferably, the bittering agent isreleased when the dosage form is tampered with and provides anunpleasant taste to the abuser upon inhalation and/or swallowing of thetampered dosage form.

[0023] In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as an irritant to discourage an abuserfrom tampering with the dosage form and thereafter inhaling, injecting,or swallowing the tampered dosage form. Preferably, the irritant isrelease when the dosage form is tampered with and provides a burning orirritating effect to the abuser upon inhalation, injection, and/orswallowing the tampered dosage form.

[0024] In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a gelling agent to discourage anabuser from tampering with the dosage form and thereafter inhaling,injecting, or swallowing the tampered dosage form. Preferably, thegelling agent is released when the dosage form is tampered with andprovides a gel-like quality to the tampered dosage form which slows theabsorption of the opioid analgesic such that an abuser is less likely toobtain a rapid “high”. In certain preferred embodiments, when the dosageform is tampered with and exposed to a small amount (e.g., less thanabout 10 ml) of an aqueous liquid (e.g., water), the dosage form will beunsuitable for injection and/or inhalation. Upon the addition of theaqueous liquid, the tampered dosage form preferably becomes thick andviscous, rendering it unsuitable for injection. The term “unsuitable forinjection” is defined for purposes of the present invention to mean thatone would have substantial difficulty injecting the dosage form (e.g.,due to pain upon administration or difficulty pushing the dosage formthrough a syringe) due to the viscosity imparted on the dosage form,thereby reducing the potential for abuse of the opioid analgesic in thedosage form. In certain embodiments, the gelling agent is present insuch an amount in the dosage form that attempts at evaporation (by theapplication of heat) to an aqueous mixture of the dosage form in aneffort to produce a higher concentration of the therapeutic agent,produces a highly viscous substance unsuitable for injection.

[0025] When nasally inhaling the tampered dosage form, the gelling agentcan become gel like upon administration to the nasal passages due to themoisture of the mucous membranes. This also makes such formulationsaversive to nasal administration, as the gel will stick to the nasalpassage and minimize absorption of the abusable substance.

[0026] In certain embodiments of the present invention, the dosage formcomprises a combination of any or all of the aforementioned aversiveagents (e.g., a bittering agent, an irritant, and/or a gelling agent) todiscourage an abuser from tampering with the dosage form and thereafterinhaling, injecting, and/or swallowing the tampered dosage form.

[0027] Embodiments specifically contemplated include bittering agent;gelling agent; irritant; bittering agent and gelling agent; bitteringagent and irritant; gelling agent and irritant; bittering agent andgelling agent; bittering agent and irritant; gelling agent and irritant;and bittering agent and gelling agent and irritant.

[0028] In certain preferred embodiments, the dosage forms are controlledrelease oral dosage forms comprising a therapeutically effective amountof an opioid analgesic and an opioid antagonist together with one ormore of the aversive agents described above such that the dosage formprovides effective pain relief for at least about 12 hours, or at leastabout 24 hours, when orally administered to a human patient.

[0029] In certain embodiments of the present invention the opioidantagonist present in the dosage form is present in a substantiallynon-releasable form (i.e., “sequestered”) when the dosage form isadministered intact as directed. Preferably, because the opioidantagonist is present in the dosage form in a substantiallynon-releasable form, it does not substantially block the analgesiceffect of the opioid agonist when the dosage form is orally administeredintact, and does not pose a risk of precipitation of withdrawal inopioid tolerant or dependent patients.

[0030] In certain embodiments of the present invention, the aversiveagent present in the dosage form is present in a substantiallynon-releasable form (i.e., “sequestered”) instead of, or in addition to,the opioid antagonist being in a substantially non-releasable form.

[0031] In other embodiments, the aversive agent may not be “sequestered”as disclosed above wherein the aversive agent is not released orminimally released from an intact dosage form, but may have a modifiedor sustained release so as not to dump the aversive agent in aparticular section of the gastrointestinal tract; e.g. the stomach,where it may cause an unwanted effect such as excessive irritation. Theaversive agent can be combined with an enteric carrier to delay itsrelease or combined with a carrier to provide a sustained release of theaversive agent. However, it is contemplated in the present inventionthat the aversive agent will preferably not have any significant sideeffect (e.g., gastrointestinal side effect) even if all of the aversiveagent is immediately released upon oral administration of an intactdosage form as directed. The aversive agent(s) can also be in the dosageform in releasable form and non-releasable form in any combination. Forexample, a dosage form can have a bittering agent, irritant, gel orcombination thereof in releasable form and non-releasable form asdisclosed in U.S. patent application entitled “Compositions And MethodsTo Prevent Abuse Of Opioids” filed Aug. 6, 2002. Likewise, theantagonist of the present invention may be in releasable form,non-releasable form or a combination of releasable form andnon-releasable form as disclosed in U.S. patent application entitled“Pharmaceutical Formulations Containing Opioid Agonist, ReleasableAntagonist, and Sequestered Antagonist” filed Aug. 6, 2002 and herebyincorporated by reference in its entirety, in combination with one ofthe aversive agents disclosed herein.

[0032] For example, the antagonist of the present invention can be anantagonist with minimal oral activity such as naloxone in releasable or“non-sequestered” form. The inclusion of such an antagonist would be adeterrent to parenteral abuse of the dosage form and the aversive agentsof the present invention (i.e., bittering agent, irritant, gellingagent) would be a deterrent to oral and nasal abuse of the dosage form.In addition, the dosage form can contain a “sequestered” antagonist suchas a bioavailable antagonist to further deter the oral and nasal abuseof the dosage form upon administration of a tampered dosage form.

[0033] The term “aversive agent” is defined for purposes of the presentinvention to mean a bittering agent, an irritant, or a gelling agent.

[0034] The term “tampered dosage form” is defined for purposes of thepresent invention to mean that the dosage form has been manipulated bymechanical, thermal, and/or chemical means which changes the physicalproperties of the dosage form, e.g., to liberate the opioid agonist forimmediate release if it is in sustained release form, or to make theopioid agonist available for inappropriate use such as administration byan alternate route, e.g., parenterally. The tampering can be, e.g., bymeans of crushing, shearing, grinding, chewing, dissolution in asolvent, heating, (e.g., greater than about 45° C.), or any combinationthereof.

[0035] The term “substantially non-releasable form” for purposes of thepresent invention refers to an opioid antagonist and/or aversive agentthat is not released or substantially not released at one hour after theintact dosage form containing an opioid agonist, an opioid antagonistand at least one aversive agent is orally administered (i.e., withouthaving been tampered with). Formulations comprising an opioid antagonistin a dosage form in a substantially non-releasable form are described inU.S. application Ser. No. 09/781,081, entitled “Tamper Resistant OralOpioid Agonist Formulations”, filed Feb. 8, 2001, the disclosure ofwhich is hereby incorporated by reference in its entirety. For purposesof the present invention, the amount released after oral administrationof the intact dosage form may be measured in-vitro via the dissolutionat 1 hour of the dosage form in 900 ml of Simulated Gastric Fluid usinga USP Type II (paddle) apparatus at 75 rpm at 37° C. Such a dosage formis also referred to as comprising a “sequestered antagonist” and/or a“sequestered aversive agent” depending on the agent or agents which arenot released or substantially not released. In certain preferredembodiments of the invention, the substantially non-releasable form ofthe antagonist and/or the aversive agent is resistant to laxatives(e.g., mineral oil) used to manage delayed colonic transit and resistantto achlorhydric states. Preferably, the aversive agent is not releasedor not substantially released 4, 8, 12 and/or 24 hours after oraladministration.

[0036] The phrase “at least partially blocking the opioid effect”, isdefined for purposes of the present invention to mean that the opioidantagonist at least significantly blocks the euphoric effect of theopioid antagonist, thereby reducing the potential for abuse of theopioid agonist in the dosage form.

[0037] The phrase “analgesic effectiveness” is defined for purposes ofthe present invention as a satisfactory reduction in or elimination ofpain, along with a tolerable level of side effects, as determined by thehuman patient.

[0038] The phrase “not substantially blocking the analgesic effect of anopioid agonist” for purposes of the present invention means that theopioid antagonist does not block the effects of the opioid agonist insufficient degree as to render the dosage form therapeutically lesseffective for providing analgesia.

[0039] The term “sustained release” is defined for purposes of thepresent invention as the release of the opioid analgesic from the oraldosage form at such a rate that blood (e.g., plasma) concentrations(levels) are maintained within the therapeutic range but below toxiclevels over an extended period of time, e.g., from about 12 to about 24hours as compared to an immediate release product. Preferably thesustained release is sufficient to provide a twice-a-day or a once-a-dayformulation.

[0040] The term “particles” of opioid antagonist, as used herein, refersto granules, spheroids, beads or pellets comprising the opioidantagonist. In certain preferred embodiments, the opioid antagonistparticles are about 0.2 to about 2 mm in diameter, more preferably about0.5 to about 2 mm in diameter.

[0041] The term “parenterally” as used herein includes subcutaneousinjections, intravenous injections, intramuscular injections,intrastemal injections, infusion techniques, or other methods ofinjection known in the art.

[0042] The term “inhaled” as used herein includes trans-mucosal,trans-bronchial, and trans-nasal abuse.

[0043] The term “bittering agent” as used herein includes a compoundused to impart a bitter taste, bitter flavor, etc., to an abuseradministering a tampered dosage form of the present invention.

[0044] The term “irritant” as used herein includes a compound used toimpart an irritating, e.g., burning or uncomfortable, sensation to anabuser administering a tampered dosage form of the present invention.

[0045] The term “gelling agent” as used herein includes a compound orcomposition used to impart gel-like or thickening quality to a tampereddosage form upon the addition of moisture or liquid.

DETAILED DESCRIPTION OF THE INVENTION

[0046] The aversive agents of the present invention are preferably foruse in connection with oral dosage forms including opioid analgesics andopioid antagonists, which provide valuable analgesia but which may beabused. This is particularly true for controlled release opioidanalgesic products which have a large dose of a desirable opioidanalgesic intended to be released over a period of time in each dosageunit. Drug abusers typically may take a controlled-release product andcrush, shear, grind, chew, dissolve and/or heat, extract or otherwisedamage the product so that the full contents of the dosage form becomeavailable for immediate absorption by injection, inhalation, and/or oralconsumption.

[0047] In certain embodiments, the present invention comprises a methodfor preventing or deterring of the abuse of opioid analgesics by theinclusion of an opioid antagonist and at least one aversive agent in thedosage form with the opioid analgesic.

[0048] In certain embodiments of the present invention wherein thedosage form includes an aversive agent comprising a bittering agent,various bittering agents can be employed including, for example andwithout limitation, natural, artificial and synthetic flavor oils andflavoring aromatics and/or oils, oleoresins and extracts derived fromplants, leaves, flowers, fruits, and so forth, and combinations thereof.Nonlimiting representative flavor oils include spearmint oil, peppermintoil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitteralmonds, menthol and the like. Also useful bittering agents areartificial, natural and synthetic fruit flavors such as citrus oilsincluding lemon, orange, lime, grapefruit, and fruit essences and soforth. Additional bittering agents include sucrose derivatives (e.g.,sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, andthe like The preferred bittering agent for use in the present inventionis Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex™(Macfarlan Smith Limited, Edinburgh, UK).

[0049] With the inclusion of a bittering agent in the formulation, theintake of the tampered with dosage form produces a bitter taste uponinhalation or oral administration which in certain embodiments spoils orhinders the pleasure of obtaining a high from the tampered dosage form,and preferably prevents the abuse of the dosage form.

[0050] A bittering agent may be added to the formulation in an amount ofless than about 50% by weight preferably less than about 10% by weight,most preferably less than about 5% by weight of the dosage form, andmost preferably in an amount ranging from about 0.1 to 1.0 percent byweight of the dosage form depending on the particular bittering agent(s)used. A dosage form including a bittering agent preferably discouragesimproper usage of the tampered dosage form by imparting a disagreeabletaste or flavor to the tampered dosage form.

[0051] In certain embodiments of the present invention wherein thedosage form includes an aversive agent comprising an irritant, variousirritants can be employed including, for example and without limitationcapsaicin, a capsaicin analog with similar type properties as capsaicin,and the like. Some capsaicin analogues or derivatives include forexample and without limitation, resiniferatoxin, tinyatoxin,heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides orguaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoylvanillylamide, or other compounds of the class known as vanilloids.Resiniferatoxin is described, for example, in U.S. Pat. No. 5,290,816(Blumberg), issued Mar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand), issuedMar. 14, 1989, describes capsaicin analogs and methods for theirpreparation. Further, U.S. Pat. No. 4,424,205 (LaHann et al.), issuedJan. 3, 1984, cite Newman, “Natural and Synthetic Pepper-FlavoredSubstances” published in 1954 as listing pungency of capsaicin-likeanalogs. Ton et al., British Journal of Pharmacology, 10, pp. 175-182(1955) discuss pharmacological actions of capsaicin and its analogs.

[0052] With the inclusion of an irritant (e.g., capsaicin) in the dosageform, when the dosage form is tampered with, the capsaicin imparts aburning or discomforting quality to the to the abuser to preferablydiscourage the inhalation, injection, or oral administration of thetampered dosage form, and preferably to prevent the abuse of the dosageform. Suitable capsaicin compositions include capsaicin (trans8-methyl-N-vanillyl-6-noneamide) or analogues thereof in a concentrationbetween about 0.00125% and 50% by weight, preferably between about 1 andabout 7.5% by weight, and most preferably, between about 1 and about 5%by weight.

[0053] In certain embodiments of the present invention wherein thedosage form includes an aversive agent comprising a gelling agent,various gelling agents can be employed including, for example andwithout limitation, sugars or sugar derived alcohols, such as mannitol,sorbitol, and the like, starch and starch derivatives, cellulosederivatives, such as microcrystalline cellulose, sodium caboxymethylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, and hydroxypropyl methylcellulose,attapulgites, bentonites, dextrins, alginates, carrageenan, gumtragacant, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin,lecithin, magnesium aluminum silicate, the carbomers and carbopols,polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinylalcohol, silicon dioxide, surfactants, mixed surfactant/wetting agentsystems, emulsifiers, other polymeric materials, and mixtures thereof,etc. In certain preferred embodiments, the gelling agent is xanthan gum.In other preferred embodiments, the gelling agent of the presentinvention is pectin. The pectin or pectic substances useful for thisinvention include not only purified or isolated pectates but also crudenatural pectin sources, such as apple, citrus or sugar beet residueswhich have been subjected, when necessary, to esterification orde-esterification, e.g., by alkali or enzymes. Preferably, the pectinsused in this invention are derived from citrus fruits such as lime,lemon, grapefruit, and orange.

[0054] With the inclusion of a gelling agent in the dosage form, whenthe dosage form is tampered with, the gelling agent preferably imparts agel-like quality to the tampered dosage form which preferably spoils orhinders the pleasure of obtaining a rapid high from the tampered dosageform due to the gel like consistency in contact with the mucousmembrane, and in certain embodiments, prevents the abuse of the dosageform by minimizing absorption, e.g. in the nasal passages. A gellingagent may be added to the formulation in a ratio of gelling agent toopioid agonist of from about 1:40 to about 40:1 by weight, preferablyfrom about 1:1 to about 30:1 by weight, and more preferably from about2:1 to about 10:1 by weight of the opioid agonist.

[0055] In certain other embodiments, the dosage form forms a viscous gelafter the dosage form is tampered with, dissolved in an aqueous liquid(from about 0.5 to about 10 ml and preferably from 1 to about 5 ml),causing the resulting mixture to have a viscosity of at least about 10cP. Most preferably, the resulting mixture will have a viscosity of atleast about 60 cP.

[0056] In certain other embodiments, the dosage form forms a viscous gelafter the dosage form is tampered with, dissolved in an aqueous liquid(from about 0.5 to about 10 ml and preferably from 1 to about 5 ml) andthen heated (e.g., greater than about 45° C.), causing the resultingmixture to have a viscosity of at least about 10 cP. Most preferably,the resulting mixture will have a viscosity of at least about 60 cP.

[0057] In certain embodiments, the dosage form may include one or moreof the aforementioned aversive agents. For safety reasons, the amount ofthe bittering agent, irritant, or gelling agent in the formulation ofthe present invention should not be toxic to humans.

[0058] Opioid antagonists useful in the present invention include, forexample and without limitation, naltrexone, naloxone, nalmefene, nalide,nalmexone, nalorphine, nalorphine dinicotinate, cyclazocine,levallorphan, pharmaceutically acceptable salts thereof, and mixturesthereof. In certain preferred embodiments, the opioid antagonist isnaloxone or naltrexone. In certain embodiments, the amount of the opioidantagonist included in the dosage form, may be about 10 ng to 275 mg.

[0059] Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to havesignificantly lower potency than as when parenterally administered. Oraldosages of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed. Weinberg, et al.,Sublingual Absorption of selected Opioid Analgesics, Clin PharmacolTher. (1988); 44:335-340.

[0060] Other opioid antagonists, for example, cyclazocine andnaltrexone, both of which have cyclopropylmethyl substitutions on thenitrogen, retain much of their efficacy by the oral route and theirdurations of action are much longer, approaching 24 hours after theiroral administration.

[0061] In the treatment of patients previously addicted to opioids,naltrexone has been used in large oral doses (over 100 mg) to preventeuphorigenic effects of opioid agonists. Naltrexone has been reported toexert strong preferential blocking action against mu over delta sites.Naltrexone is known as a synthetic congener of oxymorphone with noopioid agonist properties, and differs in structure from oxymorphone bythe replacement of the methyl group located on the nitrogen atom ofoxymorphone with a cyclopropylmethyl group. The hydrochloride salt ofnaltrexone is soluble in water up to about 100 mg/cc. Thepharmacological and pharmacokinetic properties of naltrexone have beenevaluated in multiple animal and clinical studies. See, e.g., Gonzalez JP, et al. Naltrexone: A review of its Pharmacodynamic andPharmacokinetic Properties and Therapeutic Efficacy in the Management ofOpioid Dependence. Drugs 1988; 35:192-213, hereby incorporated byreference. Following oral administration, naltrexone is rapidly absorbed(within 1 hour) and has an oral bioavailability ranging from 5-40%.Naltrexone's protein binding is approximately 21% and the volume ofdistribution following single-dose administration is 16.1 L/kg.

[0062] Naltrexone is commercially available in tablet form (Revia®,DuPont) for the treatment of alcohol dependence and for the blockade ofexogenously administered opioids. See, e.g., Revia (naltrexonehydrochloride tablets). Physician's Desk Reference 51^(st) ed.,Montvale, N.J. “Medical Economics” 1997; 51:957-959. A dosage of 50 mgRevia® blocks the pharmacological effects of 25 mg IV administeredheroin for up to 24 hours.

[0063] It is known that when coadministered with morphine, heroin orother opioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with narcotic addicts having good prognosis, as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

[0064] In certain embodiments, the aversive agent and/or the opioidantagonist included in the dosage form may be in a substantiallynon-releasable form. Where the opioid antagonist is in a substantiallynon-releasable form, the substantially non-releasable form of the opioidantagonist comprises an opioid antagonist that is formulated with one ormore pharmaceutically acceptable hydrophobic materials, such that theantagonist is not released or substantially not released during itstransit through the gastrointestinal tract when administered orally asintended, without having been tampered with.

[0065] Additionally, in certain embodiments, wherein the aversive agentis in a substantially non-releasable form, the substantiallynon-releasable form of the aversive agent comprises an aversive agentthat is formulated with one or more pharmaceutically acceptablematerials acceptable hydrophobic materials, such that the aversive agentis not released or substantially not released during its transit throughthe gastrointestinal tract when administered orally as intended, withouthaving been tampered with.

[0066] In certain embodiments of the present invention, thesubstantially non-releasable form of the opioid antagonist is vulnerableto mechanical, thermal and/or chemical tampering, e.g., tampering bymeans of crushing, shearing, grinding, chewing and/or dissolution in asolvent in combination with heating (e.g., greater than about 45° C.) ofthe oral dosage form. When the dosage form is tampered with, theintegrity of the substantially non-releasable form of the opioidantagonist will be compromised, and the opioid antagonist will be madeavailable to be released. In certain embodiments, when the dosage formis chewed, crushed or dissolved and heated in a solvent, andadministered orally, intranasally, parenterally or sublingually, theanalgesic or euphoric effect of the opioid is reduced or eliminated. Incertain embodiments, the effect of the opioid agonist is at leastpartially blocked by the opioid antagonist. In certain otherembodiments, the effect of the opioid agonist is substantially blockedby the opioid antagonist.

[0067] Additionally, the substantially non-releasable form of theaversive agent is vulnerable to mechanical, thermal and/or chemicaltampering, e.g., tampering by means of crushing, shearing, grinding,chewing and/or dissolution in a solvent in combination with heating(e.g., greater than about 45° C.) of the oral dosage form. When thedosage form is tampered with, the integrity of the substantiallynon-releasable form of the aversive agent will be compromised, and theaversive agent will be made available to be released. In certainembodiments, when the dosage form is chewed, crushed or dissolved andheated in a solvent, the release of the aversive agent hinders, detersor prevents the administration of the tampered dosage form orally,intranasally, parenterally and/or sublingually.

[0068] In certain embodiments of the present invention, ratio of theopioid agonist to the substantially non-releasable form of an opioidantagonist in the oral dosage form is such that the effect of the opioidagonist is at least partially blocked when the dosage form is chewed,crushed or dissolved in a solvent and heated, and administered orally,intranasally, parenterally or sublingually. Since the oral dosage formof certain embodiments described herein, when administered properly asintended, would not substantially release the opioid antagonist and/orthe aversive agent, the amount of such antagonist and/or aversive agentmay be varied more widely than if the opioid antagonist and/or aversiveagent is available to be released into the gastrointestinal system uponoral administration. For safety reasons, the amount of the antagonistand/or aversive agent present in a substantially non-releasable formshould not be harmful to humans even if fully released. The ratio ofparticular opioid agonist to antagonist can be determined without undueexperimentation by one skilled in the art.

[0069] In certain embodiments of the present invention, the ratio of theopioid agonist and the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight. In certain preferred embodiments, theratio is about 1:1 to about 10:1 by weight. In a preferred embodiment ofthe invention, the opioid agonist comprises oxycodone or hydrocodone andis present in the amount of about 15-45 mg and the opioid antagonistcomprises naltrexone and is present in an amount of about 0.5 to about10 mg, preferably about 0.5 to about 5 mg.

[0070] In an alternative embodiment, the opioid antagonist of thepresent invention may be included in the dosage form, such that it isanalgesically effective when orally administered, but which uponparenteral administration, does not produce analgesia, euphoria orphysical dependence. In this particular embodiment, preferably theopioid antagonist is naloxone which is in an amount which is not orallyeffective, but is parenterally effective, as described in U.S. Pat. No.3,773,955, the disclosure of which is hereby incorporated by referencein its entirety. In this embodiment, the naloxone is released from thedosage form when orally administered, but does not abolish the oralactivity of the opioid analgesic included in the dosage form.

[0071] Alternatively, the opioid antagonist of the present invention isreleased from the dosage form upon oral administration and may beincluded in the dosage form in an amount as described in WO 99/32119,the disclosure of which is hereby incorporated by reference in itsentirety, (i) which does not cause a reduction in the level of analgesiaelicited from the dosage form upon oral administration to anon-therapeutic level and (ii) which provides at least a mildlynegative, “aversive” experience in physically dependent subjects (e.g.,precipitated abstinence syndrome) when the subjects attempt to take atleast twice the usually prescribed dose at a time (and often 2-3 timesthat dose or more), as compared to a comparable dose of the opioidwithout the opioid antagonist present. Preferably, the amount ofantagonist included in the oral dosage form is less positivelyreinforcing (e.g., less “liked”) to a non-physically dependent opioidaddict than a comparable oral dosage form without the antagonistincluded. Preferably, the formulation provides effective analgesia whenorally administered. In certain preferred embodiments, the oral dosageform comprises an orally therapeutically effective dose of an opioidagonist, and an opioid antagonist in a ratio that provides a combinationproduct which is analgesically effective when the combination isadministered orally, but which is aversive in physically dependent humansubjects when administered at the same dose or at a higher dose thansaid therapeutically effective dose.

[0072] Based on a preferred ratio of naltrexone in an amount from about0.5 to about 4 mg per 15 mg of hydrocodone as described in WO 99/32119,the approximate ratio of naltrexone to 1 mg of certain opioids is setforth in Table A: TABLE A Weight Ratio of Naltrexone per Dose OpioidWeight Ratio Naltrexone per Opioid 1 mg Opioid Oxycodone 0.037 to 0.296Codeine 0.005 to 0.044 Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to1.185 Levorphanol 0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone0.056 to 0.444 Morphine 0.018 to 0.148

[0073] Based on the more preferred ratio of about 0.75 mg to about 3 mgnaltrexone per 15 mg hydrocodone of naltrexone as described in WO99/32119, the approximate ratio of naltrexone to 1 mg of certain opioidsis set forth in Table B below: TABLE B Weight Ratio of Naltrexone perDose Opioid Opioid Weight Ratio Naltrexone Oxycodone 0.056 to 0.222Codeine 0.0083 to 0.033  Hydrocodone 0.050 to 0.200 Hydromorphone 0.222to 0.889 Levorphanol 0.417 to 1.667 Meperidine 0.0056 to 0.022 Methadone 0.083 to 0.333 Morphine 0.028 to 0.111

[0074] In certain embodiments, the present invention is directed in partto an oral dosage form comprising an orally analgesically effectiveamount of an opioid agonist and an opioid antagonist in a ratios asdescribed above along with one or more aversive agents as describedherein.

[0075] In certain alternative embodiments, when the opioid antagonist isnaloxone, the opioid agonist and antagonist (e.g., naloxone) included inthe present dosage forms may be in preferred ratios as described in U.S.Pat. No. 4,457,933 to Gordon et al., the disclosure of which is herebyincorporated by reference in its entirety, such that both the oral andparenteral abuse potentials of the opioid agonist is diminished withoutappreciably affecting the oral analgetic activity of the opioid agonist.

[0076] In certain alternative embodiments, the opioid antagonist may beincluded in the dosage form in an amount such that the opioid antagonistattenuates side effects of the opioid agonist, said side effects beinganti-analgesia, hyperalgesia, hyperexcitability, physical dependence,tolerance, and combinations of any of the foregoing. For example, incertain preferred embodiments, the amount of the opioid antagonist isfrom about 100 to about 1000 fold less that the amount of the opioidagonist. Certain preferred amounts of opioid antagonist to agonist inaccordance with this embodiment are described, for example, in U.S. Pat.Nos. 5,472,943; 5,512,578; 5,580,876; 5,767,125; RE36,547; and 6,096,256all to Crain et al., the disclosures of which are herein incorporated byreference in their entireties.

[0077] All known combinations of releasable opioid antagonists withopioid agonists such as those described in U.S. Pat. No. 3,773,955(Pachter, et al.); U.S. Pat. No. 3,493,657 (Lewenstein, et al.) U.S.Pat. No. 4,457,933 (Gordon, et al.); U.S. Pat. No. 4,582,835 , (Lewis)U.S. Pat. Nos. 5,512,578; 5,472,943; 5,580,876; and 5,767,125 (Crain)and U.S. Pat. No. 4,769,372 and 4,785,000 (Kreek) can be combined withthe aversive agents disclosed herein and all of these references arehereby incorporated by reference.

[0078] All commercial products of opioid agonist and releasableantagonists can be combined with an aversive agent disclosed herein. Forexample, Talwin NX can be formulated with an aversive agent, e.g., abittering agent to reduce oral abuse as well as parenteral abuse of theopioid therein.

[0079] The opioid agonists useful in the present invention include, butare not limited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol, mixtures ofany of the foregoing, salts of any of the foregoing, and the like. Incertain embodiments, the amount of the opioid agonist in the claimedopioid composition may be about 75 ng to about 750 mg.

[0080] In certain preferred embodiments, the opioid agonist is selectedfrom the group consisting of hydrocodone, morphine, hydromorphone,oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone,buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin,tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, orsalts thereof or mixtures thereof. In certain preferred embodiments, theopioid agonist is oxycodone or hydrocodone.

[0081] In embodiments in which the opioid analgesic compriseshydrocodone, dosage forms may include analgesic doses from about 2 mg toabout 50 mg of hydrocodone bitartrate. In embodiments in which theopioid analgesic comprises hydromorphone the dosage form may includefrom about 2 mg to about 64 mg hydromorphone hydrochloride. Inembodiments in which the opioid analgesic comprises morphine, the dosageform may include from about 2.5 mg to about 800 mg morphine sulfate, byweight. In embodiments in which the opioid analgesic comprisesoxycodone, the dosage form may include from about 2.5 mg to about 320 mgoxycodone hydrochloride. The dosage form may contain more than oneopioid analgesic to provide a therapeutic effect. Alternatively, thedosage form may contain molar equivalent amounts of other salts of theopioids usefull in the present invention.

[0082] Although hydrocodone and oxycodone are effective in themanagement of pain, there has been an increase in their abuse byindividuals who are psychologically dependent on opioids or who misuseopioids for non-therapeutic reasons. Previous experience with otheropioids has demonstrated a decreased abuse potential when opioids areadministered in combination with a narcotic antagonist especially inpatients who are ex-addicts. Weinhold L L, et al. Buprenorphine Aloneand in Combination with Naltrexone in Non-Dependent Humans, Drug andAlcohol Dependence 1992; 30:263-274; Mendelson J., et al., Buprenorphineand Naloxone Interactions in Opiate-Dependent Volunteers, Clin PharmTher. 1996; 60:105-114; both of which are hereby incorporated byreference. These combinations, however, do not contain the opioidantagonist that is in a substantially non-releasable form. Rather, theopioid antagonist is released in the gastrointestinal system when orallyadministered and is made available for absorption, relying on thephysiology of the host to differentially metabolize the agonist andantagonist and negate the agonist effects.

[0083] Hydrocodone is a semisynthetic narcotic analgesic and antitussivewith multiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrdcodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

[0084] Oral hydrocodone is also available in Europe (Belgium, Germany,Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussiveagent. A parenteral formulation is also available in Germany as anantitussive agent. For use as an analgesic, hydrocodone bitartrate iscommercially available in the United States only as a fixed combinationwith non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.)for relief of moderate or moderately severe pain.

[0085] A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the opioid antagonist particlescoated with a coating that renders the antagonist substantiallynon-releasable.

[0086] Oxycodone, chemically known as4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

[0087] Oxycodone is commercially available in the United States, e.g.,as Oxycontin® from Purdue Pharma L. P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR™, also from Purdue Pharma L. P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of an opioid antagonist and one or more aversiveagents.

Preparation of Aversive Agent in a Substantially Non-Releasable Form

[0088] In certain embodiments of the present invention, an aversiveagent in a substantially non-releasable form may be prepared bycombining the aversive agent with one or more of a pharmaceuticallyacceptable hydrophobic material. For example, aversive agent particlesmay be coated with coating that substantially prevents the release ofthe aversive agent, the coating comprising the hydrophobic materials(s).Another example would be an aversive agent that is dispersed in a matrixthat renders the aversive agent substantially non-releasable, the matrixcomprising the hydrophobic materials(s). In certain embodiments, thepharmaceutically acceptable hydrophobic material comprises a cellulosepolymer selected from the group consisting of ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate and cellulose triacetate. An example ofethylcellulose is one that has an ethoxy content of 44 to 55%.Ethylcellulose may be used in the form of an alcoholic solution. Incertain other embodiments, the hydrophobic material comprises polylacticacid, polyglycolic acid or a co-polymer of the polylactic andpolyglycolic acid.

[0089] In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and tricellulose alkanylates,mono, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers include cellulose acetate having a D.S.and an acetyl content up to 21%; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

[0090] More specific cellulosic polymers include cellulose propionatehaving a D.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxylcontent of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8,an acetyl content of 13 to 15% and a butyryl content of 34 to 39%;cellulose acetate butyrate having an acetyl content of 2 to 29%, abutyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;cellulose triacylate having a D.S. of 2.9 to 3 such as cellulosetriacetate, cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate, and cellulose trioctanoate;cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedipentanoate, and coesters of cellulose such as cellulose acetatebutyrate, cellulose acetate octanoate butyrate and cellulose acetatepropionate.

[0091] Additional cellulose polymers useful for preparing an aversiveagent in a substantially non-releasable form include acetaldehydedimethyl cellulose acetate, cellulose acetate ethylcarbamate, celluloseacetate methylcarbamate, and cellulose acetate dimethylaminocelluloseacetate.

[0092] Acrylic polymers useful for preparation of the aversive agent ina substantially non-releasable form include, but are not limited to,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters (e.g., the copolymer of acrylic acid lower alkylester and methacrylic acid lower alkyl ester) containing about 0.02 to0.03 mole of a tri (lower alkyl) ammonium group per mole of the acrylicand methacrylic monomers used. An example of a suitable acrylic resin isa polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit®RS trademark. Eudragit RS30D is preferred. Eudragit® RS is a waterinsoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) andtrimethylammoniumethyl methacrylate chloride (TAM) in which the molarratio of TAM to the remaining components (EA and MM) is 1:40. Acrylicresins such as Eudragit® RS may be used in the form of an aqueoussuspension.

[0093] In certain embodiments of the invention, the acrylic polymer maybe selected from the group consisting of acrylic acid and methacrylicacid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

[0094] When the aversive agent in a substantially non-releasable formcomprises aversive agent particles coated with a coating that rendersthe aversive agent substantially non-releasable, and when a cellulosepolymer or an acrylic polymer is used for preparation of the coatingcomposition, suitable plasticizers, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate may also be admixed with the polymer. Thecoating may also contain additives such as coloring agents, talc and/ormagnesium stearate, which are well known in the coating art.

[0095] The coating composition may be applied onto the aversive agentparticles by spraying it onto the particles using any suitable sprayequipment known in the art. For example, a Wuster fluidized-bed systemmay be used in which an air jet, injected from underneath, fluidizes thecoated material and effects drying while the insoluble polymer coatingis sprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

[0096] The pharmaceutically acceptable hydrophobic material useful forpreparing an aversive agent in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesthers, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoesther or mixtures or blends of any of these.

[0097] In certain embodiments, biodegradable polymer comprises apoly(lactic/glycolic acid), a copolymer of lactic and glycolic acid,having molecular weight of about 2,000 to about 500,000 daltons. Theratio of lactic acid to glycolic acid is from about 100:0 to about25:75, with the ratio of lactic acid to glycolic acid of 65:35 beingpreferred.

[0098] Poly(lactic/glycolic acid) may be prepared by the procedure setforth in U.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure ofwhich is hereby incorporated by reference in its entirety. In brief,Ludwig prepares the copolymer by condensation of lactic acid andglycolic acid in the presence of a readily removable polymerizationcatalyst (e.g., a strong acid ion-exchange resin such as DowexHCR-W2-H). The amount of catalyst is not critical to the polymerization,but typically is from about 0.01 to about 20 parts by weight relative tothe total weight of combined lactic acid and glycolic acid. Thepolymerization reaction may be conducted without solvents at atemperature from about 100° C. to about 250° C. for about 48 to about 96hours, preferably under a reduced pressure to facilitate removal ofwater and by-products. Poly(lactic/glycolic acid) is then recovered byfiltering the molten reaction mixture in an organic solvent such asdichloromethane or acetone and then filtering to remove the catalyst.

[0099] Once the aversive agent in a substantially non-releasable form isprepared, it may be combined with an opioid agonist and the opioidantagonist (which may also be in a substantially non-releasable form asdescribed herein), along with conventional excipients known in the art,to prepare the oral dosage form of the present invention. It iscontemplated that a bittering agent or capsaicin would be the mostlikely aversive agents to be included in a sequestered formulation. Thepolymers and other ingredients above may also be utilized to formulatethe aversive agents to slow release or delay release as disclosed above.

[0100] In certain preferred embodiments of the invention, the oraldosage form is a capsule or a tablet. When being formulated as a tablet,the aversive agent and opioid agonist and opioid antagonist may becombined with one or more inert, non-toxic pharmaceutical excipientswhich are suitable for the manufacture of tablets. Such excipientsinclude, for example, an inert diluent such as lactose; granulating anddisintegrating agents such as cornstarch; binding agents such as starch;and lubricating agents such as magnesium stearate.

[0101] The oral dosage form of the present invention may be formulatedto provide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

[0102] In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist may be prepared by admixing the aversiveagent in a substantially non-releasable form with the opioid agonist andthe opioid antagonist and desirable pharmaceutical excipients to providea tablet, and then coating the tablet with a sustained-release tabletcoating.

[0103] In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an aversive agent with an aversive agent in amatrix that provides the tablets with sustained-releasing properties.

Dosage Forms

[0104] The opioid analgesic/opioid antagonist formulation in combinationwith one or more aversive agents can be formulated as an immediaterelease formulation or controlled release oral formulation in anysuitable tablet, coated tablet or multiparticulate formulation known tothose skilled in the art. The controlled release dosage form may includea controlled release material which is incorporated into a matrix alongwith the opioid analgesic and the opioid antagonist. In addition, theaversive agent may be separate from the matrix, or incorporated into thematrix.

[0105] The controlled release dosage form may optionally compriseparticles containing or comprising the opioid analgesic, wherein theparticles have diameter from about 0.1 mm to about 2.5 mm, preferablyfrom about 0.5 mm to about 2 mm. The opioid antagonist may beincorporated into these particles, or may be incorporated into a tabletor capsule containing these particles. Additionally, the aversive agentmay be incorporated into these particles, or may be incorporated into atablet or capsule containing these particles. Preferably, the particlesare film coated with a material that permits release of the opioidanalgesic at a controlled rate in an environment of use. The film coatis chosen so as to achieve, in combination with the other statedproperties, a desired in-vitro release rate. The controlled releasecoating formulations of the present invention should be capable ofproducing a strong, continuous film that is smooth and elegant, capableof supporting pigments and other coating additives, non-toxic, inert,and tack-free.

[0106] In certain embodiments, the dosage forms of the present inventioncomprise normal release matrixes containing the opioid analgesic, opioidantagonist, and the aversive agent.

Coated Beads

[0107] In certain embodiments of the present invention a hydrophobicmaterial is used to coat inert pharmaceutical beads such as nu pariel18/20 beads comprising an opioid analgesic, and a plurality of theresultant solid controlled release beads may thereafter be placed in agelatin capsule in an amount sufficient to provide an effectivecontrolled release dose when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media. The beads comprisingthe opioid analgesic may further comprise the opioid antagonist and/orone or more aversive agents, or the opioid antagonist and or one or moreaversive agents may be prepared as separate beads and then combined in adosage form including the controlled release beads comprising an opioidanalgesic, or the opioid antagonist and/or one or more aversive agentsmay be mixed in the dosage form with the controlled release beadscomprising the opioid analgesic. In preferred embodiments where theopioid analgesic and the aversive agent are mixed in a capsule asdifferent beads, the beads have an exact or similar appearance in orderto deter an abuser from manually separating the beads prior to abuse inorder to avoid the aversive substance. In tablet dosage forms, theaversive agent is preferably not included as a distinct layer which canbe easier to separate from the active agent, although the presentinvention does encompass these embodiments.

[0108] The controlled release bead formulations of the present inventionslowly release the opiold analgesic e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The controlled releaseprofile of tile formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which a plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc. The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

[0109] Spheroids or beads coated with an opioid analgesic are prepared,e.g., by dissolving the opioid analgesic in water and then spraying thesolution onto a substrate, for example, nu pariel 18/20 beads, using aWuster insert. Thereafter, the opioid antagonist and/or aversive agentis optionally added to the beads prior to coating. Optionally,additional ingredients are also added prior to coating the beads. Forexample, a product which includes hydroxypropylmethylcellulose, etc.(e.g., Opadry®, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the opioid analgesic from the hydrophobic controlledrelease coating. An example of a suitable barrier agent is one whichcomprises hydroxypropylmethylcellulose. However, any film-former knownin the art may be used. It is preferred that the barrier agent does notaffect the dissolution rate of the final product.

[0110] The beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

[0111] Plasticized hydrophobic material may be applied onto thesubstrate comprising the opioid analgesic by spraying using any suitablespray equipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid opioid analgesic when the coated substrate is exposed to aqueoussolutions, e.g. gastric fluid, is preferably applied, taking intoaccount the physical characteristics of the opioid analgesic, the mannerof incorporation of the plasticizer, etc. After coating with thehydrophobic material, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

[0112] The release of the opioid analgesic from the controlled releaseformulation of the present invention can be further influenced, i.e.,adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

[0113] The release-modifying agents which function as pore-formers maybe organic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

[0114] The controlled release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

[0115] The controlled release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

[0116] The release-modifying agent may also comprise a semi-permeablepolymer.

[0117] In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

[0118] The controlled release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 . The passageway can have any shape such as round, triangular,square, elliptical, irregular, etc.

Matrix Formulations

[0119] In certain embodiments of the present invention, the sustainedrelease formulation is achieved via a matrix optionally having acontrolled release coating as set forth herein. The present inventionmay also utilize a sustained release matrix that affords in-vitrodissolution rates of the opioid analgesic and or antagonist withindesired ranges and releases the opioid analgesic and/or antagonist in apH-dependent or pH-independent manner.

[0120] A non-limiting list of suitable sustained-release materials whichmay be included in a sustained-release matrix according to the inventionincludes hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the opioid analgesic may be used in accordance withthe present invention. Preferred sustained-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers; and cellulose ethers, especiallyhydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, ethyl acrylate, trimethylammonioethyl metbacrylate, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methylmethacrylate),poly(methacrylicacid) (anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.Certain preferred embodiments utilize mixtures of any of the foregoingsustained-release materials in the matrix of the invention.

[0121] The matrix also may include a binder. In such embodiments, thebinder preferably contributes to the sustained-release of the oxycodoneor pharmaceutically acceptable salt thereof from the sustained-releasematrix.

[0122] If an additional hydrophobic binder material is included, it ispreferably selected from natural and synthetic waxes, fatty acids, fattyalcohols, and mixtures of the same. Examples include beeswax, carnaubawax, stearic acid and stearyl alcohol. This list is not meant to beexclusive. In certain preferred embodiments, a combination of two ormore hydrophobic binder materials are included in the matrixformulations.

[0123] Preferred hydrophobic binder materials which may be used inaccordance with the present invention include digestible, long chain(C₈-C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons,such as fatty acids, fatty alcohols, glyceryl esters of fatty acids,mineral and vegetable oils, natural and synthetic waxes and polyalkyleneglycols. Hydrocarbons having a melting point of between 25° and 90° C.are preferred. Of the long-chain hydrocarbon binder materials, fatty(aliphatic) alcohols are preferred in certain embodiments. The oraldosage form may contain up to 80% (by weight) of at least onedigestible, long chain hydrocarbon.

[0124] In certain embodiments, the hydrophobic binder material maycomprise natural or synthetic waxes, fatty alcohols (such as lauryl,myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fattyacids, including but not limited to fatty acid esters, fatty acidglycerides (mono-, di-, and tri-glycerides), hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol andhydrophobic and hydrophilic materials having hydrocarbon backbones.Suitable waxes include, for example, beeswax, glycowax, castor wax andcarnauba wax. For purposes of the present invention, a wax-likesubstance is defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to about 100° C. Incertain preferred embodiments, the dosage form comprises a sustainedrelease matrix comprising an opioid analgesic; opioid antagonist; one ormore aversive agents; and at least one water soluble hydroxyalkylcellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂, aliphatic alcoholand, optionally, at least one polyalkylene glycol. The hydroxyalkylcellulose is preferably a hydroxy (C₁ to C₆) alkyl cellulose, such ashydroxypropylcellulose, hydroxypropylmethylcellulose and, especially,hydroxyethyl cellulose. The amount of the at least one hydroxyalkylcellulose in the present oral dosage form may be determined, inter alia,by the precise rate of opioid analgesic release required. The aliphaticalcohol may be, for example, lauryl alcohol, myristyl alcohol or stearylalcohol. In particularly preferred embodiments of the present oraldosage form, however, the at least one aliphatic alcohol is cetylalcohol or cetostearyl alcohol. The amount of the aliphatic alcohol inthe present oral dosage form may be determined, as above, by the preciserate of opioid analgesic release required. It may also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between about 20% and about 50% (bywt) of the aliphatic alcohol. When a polyalkylene glycol is present inthe oral dosage form, then the combined weight of the aliphatic alcoholand the polyalkylene glycol preferably constitutes between about 20% andabout 50% (by wt) of the total dosage form.

[0125] In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid analgesic from the formulation. In certainembodiments, a ratio of the hydroxyalkyl cellulose to the aliphaticalcohol/polyalkylene glycol of between 1:1 and 1:4 is preferred, with aratio of between 1:2 and 1:3 being particularly preferred.

[0126] In certain embodiments, the polyalkylene glycol may be, forexample, polypropylene glycol, or polyethylene glycol which ispreferred. The average molecular weight of the at least one polyalkyleneglycol is preferably between 1,000 and 15,000, especially between 1,500and 12,000.

[0127] Another suitable sustained-release matrix comprises analkylcellulose (especially ethylcellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

[0128] In addition to the above ingredients, a sustained-release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids and glidants that are conventionalin the pharmaceutical art.

[0129] In order to facilitate the preparation of a solid,sustained-release oral dosage form according to this invention there isprovided, in a further aspect of the present invention, a process forthe preparation of a solid, sustained-release oral dosage form accordingto the present invention comprising incorporating an opioid analgesic ina sustained-release matrix. Incorporation in the matrix may be effected,for example, by:

[0130] (a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the opioid analgesic, opioidantagonist, and at least one aversive agent;

[0131] (b) mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and

[0132] (c) optionally, compressing and shaping the granules.

[0133] The granules may be formed by any of the procedures well-known tothose skilled in the art of pharmaceutical formulation. For example, inone preferred method, the granules may be formed by wet granulating thehydroxyalkyl cellulose, opioid analgesic, opioid antagonist, and one ormore aversive agents with water. In a particularly preferred embodimentof this process, the amount of water added during the wet granulationstep is preferably between 1.5 and 5 times, especially between 1.75 and3.5 times, the dry weight of the opioid analgesic. Optionally, theopioid analgesic, opioid antagonist, and/or the one or more aversiveagents are added extragranularly.

[0134] A sustained-release matrix can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g., a wax, and incorporating a powdered drug therein.To obtain a sustained release dosage form, it may be necessary toincorporate a hydrophobic sustained-release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of sustained-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598.

[0135] The additional hydrophobic binder material may comprise one ormore water-insoluble wax-like thermoplastic substances possibly mixedwith one or more wax-like thermoplastic substances being lesshydrophobic than said one or more , water-insoluble wax-like substances.In order to achieve sustained release, the individual wax-likesubstances in the formulation should be substantially non-degradable andinsoluble in gastrointestinal fluids during the initial release phases.Useful water-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

[0136] The preparation of a suitable melt-extruded matrix according tothe present invention may, for example, include the steps of blendingthe opioid analgesic, opioid antagonist, and at least one aversiveagent, together with a sustained release material and preferably abinder material to obtain a homogeneous mixture. The homogeneous mixtureis then heated to a temperature sufficient to at least soften themixture sufficiently to extrude the same. The resulting homogeneousmixture is then extruded, e.g., using a twin-screw extruder, to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The matrixmultiparticulates are then divided into unit doses. The extrudatepreferably has a diameter of from about 0.1 to about 5 mm and providessustained release of the oxycodone or pharmaceutically acceptable saltthereof for a time period of at least about 24 hours.

[0137] An optional process for preparing the melt extruded formulationsof the present invention includes directly metering into an extruder ahydrophobic sustained release material, the opioid analgesic, opioidantagonist, one or more aversive agents, and an optional bindermaterial; heating the homogenous mixture; extruding the homogenousmixture to thereby form strands; cooling the strands containing thehomogeneous mixture; cutting the strands into matrix multiparticulateshaving a size from about 0.1 mm to about 12 mm; and dividing saidparticles into unit doses. In this aspect of the invention, a relativelycontinuous manufacturing procedure is realized.

[0138] Optionally, the opioid antagonist and/or the one or more aversiveagents may be prepared as separate multiparticulates (without the opioilagonist) and thereafter the multiparticulates may be combined withmultiparticulates comprising opioid analgesic (without the antagonistand/or the one or more aversive agents) in a dosage form.

[0139] Plasticizers, such as those described above, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, lubricants and thelike may be included in the sustained release matrices of the presentinvention as desired. The amounts included will depend upon the desiredcharacteristic to be achieved.

[0140] The diameter of the extruder aperture or exit port can beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0141] A melt extruded matrix multiparticulate system can be, forexample, in the form of granules, spheroids or pellets depending uponthe extruder exit orifice. For purposes of the present invention, theterms “melt-extruded matrix multiparticulate(s)” and “melt-extrudedmatrix multiparticulate system(s)” and “melt-extruded matrix particles”shall refer to a plurality of units, preferably within a range ofsimilar size and/or shape and containing one or more active agents andone or more excipients, preferably including a hydrophobic sustainedrelease material as described herein. Preferably the melt-extrudedmatrix multiparticulates will be of a range of from about 0.1 to about12 mm in length and have a diameter of from about 0.1 to about 5 mm. Inaddition, it is to be understood that the melt-extruded matrixmultiparticulates can be any geometrical shape within this size range.In certain embodiments, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

[0142] In one preferred embodiment, oral dosage forms are prepared thatinclude an effective amount of melt-extruded matrix multiparticulateswithin a capsule. For example, a plurality of the melt-extruded matrixmultiparticulates may be placed in a gelatin capsule in an amountsufficient to provide an effective sustained release dose when ingestedand contacted by gastrointestinal fluid.

[0143] In another embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tabletingequipment using standard techniques. Techniques and compositions formaking tablets (compressed and molded), capsules (hard and soft gelatin)and pills are also described in Remington's Pharmaceutical Sciences,(Arthur Osol, editor), 1553-1593 (1980).

[0144] In yet another preferred embodiment, the extrudate can be shapedinto tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et.al.).

[0145] Optionally, the sustained-release matrix multiparticulatesystems, tablets, or capsules can be coated with a sustained releasecoating such as the sustained release coatings described herein. Suchcoatings preferably include a sufficient amount of hydrophobic and/orhydrophilic sustained-release material to obtain a weight gain levelfrom about 2 to about 25 percent, although the overcoat may be greaterdepending upon, e.g., the desired release rate. The coating canoptionally contain one or more of the aversive agents. In suchembodiments, an optional second overcoat can be applied as to minimizethe perception of the aversive agent when a dosage form of the presentinventions administered intact.

[0146] The dosage forms of the present invention may further includecombinations of melt-extruded matrix multiparticulates containing anopioid analgesic; an opioid antagonist; one or more aversive agents; ormixtures thereof. Furthermore, the dosage forms can also include anamount of an immediate release opioid analgesic for prompt therapeuticeffect. The immediate release opioid analgesic may be incorporated,e.g., as separate multiparticulates within a gelatin capsule, or may becoated on the surface of, e.g., melt extruded matrix multiparticulates.

[0147] The sustained-release profile of the melt-extruded formulationsof the invention can be altered, for example, by varying the amount ofsustained-release material, by varying the amount of plasticizerrelative to other matrix constituents, by varying the amount ofhydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

[0148] In other embodiments of the invention, melt-extruded formulationsare prepared without the inclusion of the opioid analgesic; opioidantagonist; one or more aversive agents; or mixtures thereof; which isadded thereafter to the extrudate. Such formulations typically will havethe opioid analgesic; opioid antagonist; one or more aversive agents; ormixtures thereof blended together with the extruded matrix material, andthen the mixture would be tableted in order to provide a slow releaseformulation. Such formulations may be advantageous, for example, whenthe opioid analgesic; opioid antagonist; one or more aversive agents; ormixtures thereof included in the formulation is sensitive totemperatures needed for softening the hydrophobic material and/or theretardant material.

[0149] Typical melt-extrusion production systems suitable for use inaccordance with the present invention include a suitable extruder drivemotor having variable speed and constant torque control, start-stopcontrols, and a meter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such as atwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into the matrixmultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C. W. Brabender Instruments,Inc. of South Hackensack, N.J. Other suitable apparatus will be apparentto those of ordinary skill in the art.

[0150] A further aspect of the invention is related to the preparationof melt-extruded matrix multiparticulates as set forth above in a mannerwhich controls the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the opioid analgesic, opioid antagonist, one or more aversiveagents, or mixtures thereof may be altered.

[0151] Thus, in a further aspect of the invention, the melt-extrudedproduct is prepared in a manner which substantially excludes air duringthe extrusion phase of the process. This may be accomplished, forexample, by using a Leistritz extruder having a vacuum attachment. Theextruded matrix multiparticulates prepared according to the inventionusing the Leistritz extruder under vacuum provides a melt-extrudedproduct having different physical characteristics. In particular, theextrudate is substantially non-porous when magnified, e.g., using ascanning electron microscope which provides an SEM (scanning electronmicrograph). Such substantially non-porous formulations may provide afaster release of the therapeutically active agent, relative to the sameformulation prepared without vacuum. SEMs of the matrixmultiparticulates prepared using an extruder under vacuum appear verysmooth, and the multiparticulates tend to be more robust than thosemultiparticulates prepared without vacuum. It has been observed that inat least certain formulations, the use of extrusion under vacuumprovides an extruded matrix multiparticulate product which is morepH-dependent than its counterpart formulation prepared without vacuum.

[0152] Alternatively, the melt-extruded product is prepared using aWerner-Pfleiderer twin screw extruder.

[0153] In certain embodiments, a spheronizing agent is added to agranulate or matrix multiparticulate and then spheronized to producesustained release spheroids. The spheroids are then optionallyovercoated with a sustained release coating by methods such as thosedescribed above.

[0154] Spheronizing agents which may be used to prepare the matrixmultiparticulate formulations of the present invention include anyart-known spheronizing agent. Cellulose derivatives are preferred, andmicrocrystalline cellulose is especially preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (TradeMark, FMC Corporation). The spheronizing agent ispreferably included as about 1 to about 99% of the matrixmultiparticulate by weight.

[0155] In certain embodiments, in addition to the opioid analgesic,opioid antagonist, one or more aversive agents, and spheronizing agent,the spheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxy propyl cellulose, are preferred. Additionally(or alternatively) the spheroids may contain a water insoluble polymer,especially an acrylic polymer, an acrylic copolymer, such as amethacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.

[0156] In certain embodiments, a sustained release coating is applied tothe sustained release spheroids, granules, or matrix multiparticulates.In such embodiments, the sustained-release coating may include a waterinsoluble material such as (a) a wax, either alone or in admixture witha fatty alcohol; or (b) shellac or zein. The coating is preferablyderived from an aqueous dispersion of the hydrophobic sustained releasematerial.

[0157] In certain embodiments, it is necessary to overcoat the sustainedrelease spheroids, granules, or matrix multiparticulates comprising theopioid analgesic, opioid antagonist, one or more aversive agents, andsustained release carrier with a sufficient amount of the aqueousdispersion of, e.g., alkylcellulose or acrylic polymer, to obtain aweight gain level from about 2 to about 50%, e.g., about 2 to about 25%,in order to obtain a sustained-release formulation. The overcoat may belesser or greater depending upon, e.g., the desired release rate, theinclusion of plasticizer in the aqueous dispersion and the manner ofincorporation of the same. Cellulosic materials and polymers, includingalkylcelluloses, are sustained release materials well suited for coatingthe sustained release spheroids, granules, or matrix multiparticulatesaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

[0158] One commercially-available aqueous dispersion of ethylcelluloseis Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® isprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is necessary to intimately mix the Aquacoat® with a suitableplasticizer prior to use.

[0159] Another aqueous dispersion of ethylcellulose is commerciallyavailable as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). Thisproduct is prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(dibutyl sebacate), and stabilizer (oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly to thesustained release spheroids, granules, or matrix multiparticulates.

[0160] In other preferred embodiments of the present invention, thesustained release material comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

[0161] In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inthe National Formulary (NF) XVII as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. In order to obtain a desirable dissolution profile, itmay be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties, such as different molarratios of the quaternary ammonium groups to the neutral (meth)acrylicesters.

[0162] Certain methacrylic acid ester-type polymers are useful forpreparing pH-dependent coatings which may be used in accordance with thepresent invention. For example, there are a family of copolymerssynthesized from diethylaminoethyl methacrylate and other neutralmethacrylic esters, also known as methacrylic acid copolymer orpolymeric methacrylates, commercially available as Eudragit® from RöhmGMBH and Co. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit S does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

[0163] In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Rohmunder the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

[0164] The Eudragit® RL/RS dispersions of the present invention may bemixed together in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L. Inembodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic sustained release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the sustained-release coating. For example, becauseethyl-cellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining sustained-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

[0165] Examples of suitable plasticizers for ethylcellulose includewater insoluble plasticizers such as dibutyl sebacate, diethylphthalate, triethyl citrate, tuibutyl citrate, and triacetin, althoughit is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may beused. Triethyl citrate is an especially preferred plasticizer for theaqueous dispersions of ethyl cellulose of the present invention.

[0166] Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

[0167] In certain embodiments, the uncoated/coated sustained releasespheroids, granules, or matrix multiparticulates containing the opioidanalgesic; opioid antagonist; and one or more aversive agents; are cureduntil an endpoint is reached at which the sustained release spheroids,granules, or matrix multiparticulates provide a stable dissolution ofthe opioid. The curing endpoint may be determined by comparing thedissolution profile (curve) of the dosage form immediately after curingto the dissolution profile (curve) of the dosage form after exposure toaccelerated storage conditions of, e.g., at least one month at atemperature of 40° C. and a relative humidity of 75%. Cured formulationsare described in detail in U.S. Pat. Nos. 5,273,760; 5,286,493;5,500,227; 5,580,578; 5,639,476; 5,681,585; and 6,024,982. Otherexamples of sustained-release formulations and coatings which may beused in accordance with the present invention include those described inU.S. Pat. Nos. 5,324,351; 5,356,467; and 5,472,712.

[0168] In addition to the above ingredients, the spheroids, granules, ormatrix multiparticulates may also contain suitable quantities of othermaterials, e.g., diluents, lubricants, binders, granulating aids, andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the formulation if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

[0169] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms are describedin the Handbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

[0170] It has further been found that the addition of a small amount oftalc to the sustained release coating reduces the tendency of theaqueous dispersion to stick during processing, and acts as a polishingagent.

Osmotic Dosage Forms

[0171] Sustained release dosage forms according to the present inventionmay also be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer(containing the opioid analgesic and optionally the opioid antagonistand or one or more aversive agents) and a delivery or push layer (whichmay contain the opioid antagonist and/or one or more aversive agents),wherein the bilayer core is surrounded by a semipermeable wall andoptionally having at least one passageway disposed therein.

[0172] The expression “passageway” as used for the purpose of thisinvention, includes aperture, orifice, bore, pore, porous elementthrough which the opioid analgesic (with or without the antagonist) canbe pumped, diffuse or migrate through a fiber, capillary tube, porousoverlay, porous insert, microporous member, or porous composition. Thepassageway can also include a compound that erodes or is leached fromthe wall in the fluid environment of use to produce at least onepassageway. Representative compounds for forming a passageway includeerodible poly(glycolic) acid, or poly(lactic) acid in the wall; agelatinous filament; a water-removable poly(vinyl alcohol); leachablecompounds such as fluid-removable pore-forming polysaccharides, acids,salts or oxides. A passageway can be formed by leaching a compound fromthe wall, such as sorbitol, sucrose, lactose, maltose, or fructose, toform a sustained-release dimensional pore-passageway. The passageway canhave any shape, such as round, triangular, square and elliptical, forassisting in the sustained metered release of opioid analgesic from thedosage form. The dosage form can be manufactured with one or morepassageways in spaced-apart relation on one or more surfaces of thedosage form. A passageway and equipment for forming a passageway aredisplosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and4,088,864. Passageways comprising sustained-release dimensions sized,shaped and adapted as a releasing-pore formed by aqueous leaching toprovide a releasing-pore of a sustained-release rate are disclosed inU.S. Pat. Nos. 4,200,098 and 4,285,987.

[0173] In certain embodiments, the bilayer core comprises a drug layerwith opioid analgesic and a displacement or push layer optionallycontaining the antagonist and/or one or more aversive agents. Theantagonist and/or one or more aversive agents may optionally be includedin the drug layer instead of or in addition to being included in thepush layer. In certain embodiments the drug layer may also comprise atleast one polymer hydrogel. The polymer hydrogel may have an averagemolecular weight of between about 500 and about 6,000,000. Examples ofpolymer hydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n).H₂O wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

[0174] In certain embodiments of the present invention, the delivery orpush layer comprises an osmopolymer. Examples of an osmopolymer includebut are not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the contents of the drug layer from theosmotic dosage form.

[0175] The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

[0176] The push layer may optionally include ahydroxypropylalkylcellulose possessing a 9,000 to 450,000 number-averagemolecular weight. The hydroxypropylalkylcellulose is represented by amember selected from the group consisting ofhydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylisopropyl cellulose, hydroxypropylbutylcellulose, andhydroxypropylpentylcellulose.

[0177] The push layer may also optionally comprise an antioxidant toinhibit the oxidation of ingredients. Some examples of antioxidantsinclude but are not limited to a member selected from the groupconsisting of ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole,butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid,potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid,potassium ascorbate, vitamin E, 4- hloro-2,6-ditertiary butylphenol,alphatocopherol, and propylgallate.

[0178] In certain alternative embodiments, the dosage form comprises asubstantially homogenous core comprising opioid analgesic, an opioidantagonist, one or more aversive agents, a pharmaceutically acceptablepolymer (e.g., polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thesubstantially homogenous core is surrounded by a semipermeable wallhaving a passageway (as defined above) for the release of the opioidanalgesic, the opioid antagonist, and the one or more aversive agents.

[0179] In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

[0180] Additional semipermeable polymers for the purpose of thisinvention comprise acetaldehyde dimethycellulose acetate, celluloseacetate ethylcarbamate, cellulose acetate methylcarbamate, cellulosediacetate, propylcarbamate, cellulose acetate diethylaminoacetate;semipermeable polyamide; semipermeable polyurethane; semipermeablesulfonated polystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (Cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

[0181] In certain embodiments, preferably the semipermeable wall isnontoxic, inert, and it maintains its physical and chemical integrityduring the dispensing life of the drug. In certain embodiments, thedosage form comprises a binder. An example of a binder includes, but isnot limited to a therapeutically acceptable vinyl polymer having a 5,000to 350,000 viscosity-average molecular weight, represented by a memberselected from the group consisting of poly-n-vinylamide,poly-n-vinylacetamide, poly(vinyl pyrrolidone), also known aspoly-n-vinylpyrrolidone, poly-n-vinylcaprolactone,poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinyl-pyrrolidonecopolymers with a member selected from the group consisting of vinylacetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate,vinyl laureate, and vinyl stearate. Other binders include for example,acacia, starch, gelatin, and hydroxypropylalkylcellulose of 9,200 to250,000 average molecular weight.

[0182] In certain embodiments, the dosage form comprises a lubricant,which may be used during the manufacture of the dosage form to preventsticking to die wall or punch faces. Examples of lubricants include butare not limited to magnesium stearate, sodium stearate, stearic acid,calcium stearate, magnesium oleate, oleic acid, potassium oleate,caprylic acid, sodium stearyl fumarate, and magnesium palmitate.

Transdermal Delivery Systems

[0183] The formulations of the present invention may be formulated as atransdermal delivery system, such as transdermal patches. In certainembodiments of the present invention, a transdermal patch comprises anopioid agonist contained in a reservoir or a matrix, and an adhesivewhich allows the transdermal device to adhere to the skin, allowing thepassage of the active agent from the transdermal device through the skinof the patient, with the inclusion of the aversive agents and opioidantagonists as disclosed herein which are not releasable when the dosageform is administered intact but which are releasable when the dosageform is broken or tampered with in order to release the opioid from thetransdermal system.

[0184] Transdermal delivery system providing a controlled-release of anopioid agonist is known. For example, Duragesic® patch (commerciallyavailable from Janssen Pharmaceutical) contains an opioid agonist(fentanyl) and is said to provide adequate analgesia for up to 48 to 72hours (2 to 3 days). This formulation can be reformulated with anaversive agent and antagonist as disclosed herein.

[0185] There are several types of transdermal formulations ofbuprenorphine reported in the literature. See, for example, U.S. Pat.No. 5,240,711 (Hille et al.), U.S Pat. No. 5,225,199 (Hidaka et al.),U.S. Pat. No. 5,069,909 (Sharma et al.), U.S. Pat. No. 4,806,341 (Chienet al.), and U.S. Pat. No. 5,026,556 (Drust et al.), all of which arehereby incorporated by reference. These transdermal devices can also bereformulated with the aversive agents and antagonists as disclosedherein.

[0186] The transdermal delivery system used in the present invention mayalso be prepared in accordance with U.S. Pat. No. 5,069,909 (Sharma etal.), hereby incorporated by reference. This patent describes alaminated composite for administering buprenorphine transdermally totreat pain. The transdermal delivery system used in the presentinvention may also be prepared in accordance with U.S. Pat. No.4,806,341 (Chien et al.), hereby incorporated by reference. This patentdescribes a transdermal morphinan narcotic analgesic or antagonist(including buprenorphine) pharmaceutical polymer matrix dosage unithaving a backing layer which is substantially impervious to thebuprenorphine, and a polymer matrix disc layer which is adhered to thebacking layer and which has microdispersed therein effective dosageamounts of the buprenorphine.

[0187] The transdermal delivery system used in the present invention mayalso be that described in U.S. Pat. No. 5,026,556 (Drust et al.), herebyincorporated by reference. Therein, compositions for the transdermaldelivery of buprenorphine comprise buprenorphine in a carrier of a polarsolvent material selected from the group consisting of C₃-C₄ diols,C₃-C₆ triols, and mixtures thereof, and a polar lipid material selectedfrom the group consisting of fatty alcohol esters, fatty acid esters,and mixtures thereof; wherein the polar solvent material and the lipidmaterial are present in a weight ratio of solvent material:lipidmaterial of from 60:40 to about 99:1. The transdermal delivery systemused in the present invention may also be that described in U.S. Pat.No. 4,588,580 (Gale, et. al.), hereby incorporated by reference. Thatsystem comprises a reservoir for the drug having a skin proximal,material releasing surface area in the range of about 5-100 cm² andcontaining between 0.1 and 50% by weight of a skin permeable form of thebuprenorphine. The reservoir contains an aqueous gel comprising up toabout 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, andrelease rate controlling means disposed in the flow path of the drug tothe skin which limits the flux of the buprenorphine from the systemthrough the skin.

[0188] The transdermal delivery system used in the present invention mayalso be that described in PCT/US01/04347 to Oshlack et al.

[0189] The present invention is contemplated to encompass alltransdermal formulations, e.g., the technologies described above, withthe inclusion of an aversive agent and antagonist, such that the dosageform deters abuse of the opioid therein.

[0190] The aversive agent and antagonist in non-releasable form whenadministered intact can be formulated in accordance with U.S. Pat. No.5,149,538 to Granger, hereby incorporated by reference. Alternatively,the aversive agent and the opioid agonist can be separated from theopioid by a layer which becomes disrupted when the dosage form istampered with, thereby mixing the aversive agent with the opioidagonist. Alternatively, a combination of both systems can be used.

Suppositories

[0191] The controlled release formulations of the present invention maybe formulated as a pharmaceutical suppository for rectal administrationcomprising an opioid analgesic, opioid antagonist, and at least oneaversive agent in a controlled release matrix, and a suppository vehicle(base). Preparation of controlled release suppository formulations isdescribed in, e.g., U.S. Pat. No. 5,215,758.

[0192] The suppository base chosen should be compatible with theagent(s) of the present invention. Further, the suppository base ispreferably non-toxic and nonirritating to mucous membranes, melts ordissolves in rectal fluids, and is stable during storage.

[0193] In certain preferred embodiments of the present invention forboth water-soluble and water-insoluble drugs, the suppository basecomprises a fatty acid wax selected from the group consisting of mono-,di- and triglycerides of saturated, natural fatty acids of the chainlength C₁₂ to C₁₈.

[0194] In preparing the suppositories of the present invention otherexcipients may be used. For example, a wax may be used to form theproper shape for administration via the rectal route. This system canalso be used without wax, but with the addition of diluent filled in agelatin capsule for both rectal and oral administration.

[0195] Examples of suitable commercially available mono-, di- andtriglycerides include saturated natural fatty acids of the 12-18 carbonatom chain sold under the trade name Novata T M (types AB, AB, B,BC, BD,BBC, E, BCF, C, D and 299), manufactured by Henkel, and Witepsol T M(types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35,W45, S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel.

[0196] Other pharmaceutically acceptable suppository bases may besubstituted in whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent by weight of the totalweight of the suppository. Preferably, the amount of base in thesuppository is from about 65 percent to about 80 percent, by weight ofthe total weight of the suppository.

[0197] In certain embodiments of the dosage forms of the presentinvention may also include a surfactant. Surfactants useful inaccordance with the present invention, include for example, ionic andnonionic surfactants or wetting agents commonly used in the formulationof pharmaceuticals, including but not limited to castor oil derivatives,cholesterol, polyglycolyzed glycerides, acetylated monoglycerides,sorbitan fatty acid esters, poloxamers, polysorbates, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene compounds, monoglycerides orethoxylated derivatives thereof, diglycerides or polyoxyethylenederivatives thereof, sodium docusate, sodium laurylsulfate, cholic acidor derivatives thereof, ethoxylated alcohols, ethoxylated esters,ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols,ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters, alkali metal sulfates, quaternary ammonium compounds,amidoamines, and aminimides, simethicone, lecithins, alcohols,phospholipids, and mixtures thereof.

[0198] Mixed surfactant/wetting agents useful in accordance with thepresent invention include, for example, sodium laurylsulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG6000/stearic acid, etc.

[0199] In certain embodiments of the present invention, the dosage formmay also include an emulsifying agent. Emulsifying agents useful inaccordance with the present invention include, for example,monoglycerides, sucrose/fatty acid esters, polyglycerol/fatty acidesters, sorbitan/fatty acid esters, lecithins, potassium and sodiumsalts of rosin acids and higher fatty acids, as well as sulfates andsulfonates of these acids, amine salts of hydroxylamines of long-chainfatty acid esters, quaternary ammonium salts such asstearyl-dimethylbenzylammonium chloride andtridecylbenzenehydroxyethylimidazole chloride, phosphoric esters ofhigher alcohols such as capryl and octyl alcohol, and monoesters ofoleic acid and pentaerythritol such as sorbitan monooleates, andmixtures thereof.

[0200] The oral dosage form and methods for use of the present inventionmay further include, in addition to an opioid analgesic and opioidantagonist, one or more drugs that may or may not act synergisticallywith the opioid analgesic. Thus, in certain embodiments, a combinationof two opioid analgesics may be included in the dosage form. Forexample, the dosage form may include two opioid analgesics havingdifferent properties, such as half-life, solubility, potency, and acombination of any of the foregoing.

[0201] In yet further embodiments, one or more opioid analgesic isincluded and a further non-opioid drug is also included. Such non-opioiddrugs would preferably provide additional analgesia, and include, forexample, aspirin, acetaminophen; non-steroidal anti-inflammatory drugs(“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate(NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphanor dextrorphan, or ketamine; cyclooxygenase-II inhibitors (“COX-Iinhibitors”); and/or glycine receptor antagonists.

[0202] In certain preferred embodiments of the present invention, theinvention allows for the use of lower doses of the opioid analgesic byvirtue of the inclusion of an additional non-opioid analgesic, such asan NSAID or a COX-2 inhibitor. By using lower amounts of either or bothdrugs, the side effects associated with effective pain management inhumans are reduced.

[0203] Suitable non-steroidal anti-inflammatory agents, includingibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Useful dosages of these drugs arewell known to those skilled in the art.

[0204] N-methyl-D-aspartate (NMDA) receptor antagonists are well knownin the art, and encompass, for example, morphinans such asdextromethorphan or dextrorphan, ketamine, or pharmaceuticallyacceptable salts thereof. For purposes of the present invention, theterm “NMDA antagonist” is also deemed to encompass drugs that block amajor intracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM₁ or GT_(1b) a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g. narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et.al. patents.

[0205] The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.).

[0206] COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as vioxx), nabumetone (produg for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

[0207] In yet further embodiments, a non-opioid drug can be includedwhich provides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

[0208] The invention disclosed herein is meant to encompass the use pfany pharmaceutically acceptable salts thereof of the disclosed opioidanalgesics. The pharmaceutically acceptable salts include, but are notlimited to, metal salts such as sodium salt, potassium salt, secium saltand the like; alkaline earth metals such as calcium salt, magnesium saltand the like; organic amine salts such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

[0209] Some of the opioid analgesics disclosed herein may contain one ormore asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms. The present invention isalso meant to encompass the use of any of such possible forms as well astheir racemic and resolved forms and mixtures thereof. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. The use of alltautomers are intended to be encompassed by the present invention aswell.

[0210] The oral dosage forms of the present invention may be in the formof tablets, troches, lozenges, powders or granules, hard or softcapsules, microparticles (e.g., microcapsules, microspheres and thelike), buccal tablets, etc.

[0211] In certain embodiments, the present invention provides for amethod of preventing abuse of an oral controlled release dosage form ofan opioid analgesic comprising preparing the dosage forms as describedabove.

[0212] In certain embodiments, the present invention provides for amethod of preventing diversion of an oral controlled release dosage formof an opioid analgesic comprising preparing the dosage forms asdescribed above.

[0213] In certain embodiments, the present invention provides for amethod of treating pain by administering to a human patient the dosageforms described above.

[0214] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 A 20 mg Oxycodone Formulation is Prepared Containing Naloxoneas the Antagonist and Xanthan Gum as the Aversive Agent

[0215] In this example, a small amount of xanthan gum is added to theoxycodone formulation during the granulation process. Other gellingagents such as curdlan, carrageenan, alginates, pectin, gelatin,furcelleran, agar, guar gum, locust bean gum, tara gum, tragacanth,acacia, glucomannans, karaya, starch and starch derivatives, egg whitepowder, lacto albumin, soy protein, Jargel, gellan gum, welan gum,rhamsan gum, and the like, could also be used as gelling agents. Othersemi-synthetic materials such as chitosan, pullulan, polylaevulan,hydroxypropyl cellulose, methylcellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, ethylhydroxyethyl cellulose, all etherderivatives of cellulose, and the like, could also be used as alternategelling materials. The formulation of Example 1 is listed in Table 1below. TABLE 1 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl20.0  209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0  50.0 EudragitRS30D (solids) 10.0 100   Triacetin 2.0  20.0 Naloxone HCl 0.61   6.12** Xanthan gum 9.0  90.0 Stearyl Alcohol 25.0 250.0 Talc 2.5 25.0 Magnesium Stearate 1.25  12.5 Opadry Pink Y-S-14518A 5.0  50.0

[0216] Process

[0217] 1. Dispersion: Dissolve naloxone HCl in water and the solution isadded to the Eudragit/Triacetin dispersion.

[0218] 2. Granulation: Spray the Eudragit/Triacetin dispersion onto theoxycodone HCl, Spray Dried Lactose, xanthan gum and Povidone using afluid bed granulator.

[0219] 3. Milling: Discharge the granulation and pass through a mill

[0220] 4. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0221] 5. Milling: Pass the cooled granulation through a mill.

[0222] 6. Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0223] 7. Compression: Compress the granulation into tablets using atablet press.

EXAMPLE 2 A 40 mg Oxycodone Formulation was Prepared Containing Naloxoneas the Antagonist and Xanthan Gum as the Aversive Agent

[0224] To determine the effect of varying amount of xanthan gum on thegelling property and dissolution rate of an oxycodone tablet, threelevels of xanthan gum were added to 40 mg oxycodone granulation andcompressed into tablets. Oxycodone recovery from water extraction of thetablet and the drug release rate were determined. The oxycodonegranulation formulation of Example 2 is listed in Table 2 below. TABLE 2Ingredients Amt/Unit (mg) Oxycodone HCl 40.0 Spray Dried Lactose 39.25Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 Naloxone HCL 0.9Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Total 125.9

[0225] Examples 2A to 2C were prepared adding different amounts (3 mg, 5mg, and 9 mg) of xanthan gum to a 125.9 mg oxycodone granulation ofExample 2. Ingredients Amt/Unit (mg) EXAMPLE 2A Oxycodone granulation125.9 Xanthan gum 3 Total 128.9 EXAMPLE 2B Oxycodone granulation 125.9Xanthan gum 5 Total 130.9 EXAMPLE 2C Oxycodone granulation 125.9 Xanthangum 9 Total 134.9

[0226] Process

[0227] 1. Dispersion: Dissolve naloxone HCl in water and the solution isadded to the Eudragit/Triacetin dispersion.

[0228] 2. Granulation: Spray the Eudragit/Triacetin dispersion onto theOxycodone HCl, Spray Dried Lactose and Povidone using a fluid bedgranulator.

[0229] 3. Milling: Discharge the granulation and pass through a mill.

[0230] 4. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0231] 5. Milling: Pass the cooled granulation through a mill.

[0232] 6. Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0233] 7. Add xanthan gum (3 levels) to the granulation and mix well.

[0234] 8. Compression: Compress the granulation into tablets using atablet press.

EXAMPLE 3

[0235] The granulation of Example 2 was compressed into tablets using atablet press without the addition of xanthan gum, and Examples 2, 2A-Cwere tested under the following dissolution conditions and gave theresults listed in Table 3 below.

[0236] 1. Apparatus: USP Type II (paddle), 150 rpm.

[0237] 2. Medium: 700 ml SGF for first hour, thereafter made 900 ml withphosphate buffer to pH 7.5.

[0238]3. Sampling time: 1,2,4,8,12,18 and 24 hours.

[0239] 4. Analytical: High Performance Liquid Chromatography. TABLE 3Dissolution Results % Dissolved Ex. 2A Ex. 2B Ex. 2C Ex. 2 Time (3 mg (5mg (9 mg (no xanthan (hrs) xanthan) xanthan) xanthan) added) Spec 1 4843 46 45 28-58 4 86 73 79 75 55-88 12 101 98 99 93 >80

[0240] The dissolution results show that all the tablets prepared havesimilar dissolution profiles. The inclusion of xanthan gum does notappear to substantially change the oxycodone dissolution rate.

[0241] When 1 mL of water was added to the tablets containing xanthangum on a tea spoon, the solution was not viscous. However, when thesamples were heated and allowed to cool, the samples became veryviscous. It was very difficult to withdraw this gel-like solution into asyringe for injection.

EXAMPLE 4 A 20 mg Oxycodone Formulation Containing Naloxone as theAntagonist and a Bittering Agent as the Aversive Agent is Prepared

[0242] In this example, a small amount of denatonium benzoate is addedto an oxycodone formulation during the granulation process. The bittertaste would reduce the abuse of oxycodone by oral or intranasal route.The oxycodone formulation of Example 4 is listed in Table 4 below. TABLE4 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0  209.6*Spray Dried Lactose 59.25 592.5 Povidone 5.0  50.0 Eudragit RS30D(solids) 10.0 100   Triacetin 2.0  20.0 Naloxone HCl 0.61    6.12**Denatonium benzoate 0.07  0.68 Stearyl Alcohol 25.0 250.0 Talc 2.5  25.0Magnesium Stearate 1.25  12.5 Opadry Pink Y-S-14518A 5.0  50.0

[0243] Process

[0244] 1. Dispersion: Dissolve naloxone HCL and denatonium benzoate inwater and the solution is added to the Eudragit/Triacetin dispersion.

[0245] 2. Granulation: Spray the Eudragit/Triacetin dispersion onto theOxycodone HCl, Spray Dried Lactose and Povidone using a fluid bedgranulator.

[0246] 3. Milling: Discharge the granulation and pass through a mill.

[0247] 4. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0248] 5. Milling: Pass the cooled granulation through a mill.

[0249] 6. Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0250] 7. Compression: Compress the granulation into tablets using atablet press.

EXAMPLE 5

[0251] In Example 5, a substantially non-releasable form of a bitteringagent (denatonium benzoate) is prepared by coating denatonium benzoateparticles with a coating that renders the denatonium benzoatesubstantially non-releasable. The formulation of Example 5 is listed inTable 5 below. TABLE 5 Amt/unit Ingredients (mg) LOADING denatoniumbenzoate  0.07 Sugar Spheres (30/35 mesh) 50.0 Opadry White Y-5-7068 2.5 Purified Water  42.5* OVERCOATING Opadry White Y-5-7068  3.02Purified Water  17.11* NON-RELEASE COATING (FOR RENDERING BITTERINGAGENT SUBSTANTIALLY NON- RELEASABLE) Eudragit RS30D (dry wt.)  12.10Triethyl Citrate  2.42 Talc  4.84 Purified Water  49.21* OVERCOATINGOpadry White Y-5-7068  4.12 Purified Water  23.35* Total  79.07

[0252] Process:

[0253] 1. Solution Preparation Dissolve the denatonium benzoate inPurified Water. Once dissolved, add the Opadry White and continue mixinguntil a homogeneous dispersion is yielded.

[0254] 2. Loading Apply the above dispersion onto the Sugar Spheresusing a fluid bed coating machine.

[0255]3. Overcoating Prepare an overcoating solution by dispersingOpadry White in Purified Water. Apply this dispersion over the sugarspheres loaded with denatonium benzoate using a fluid bed coatingmachine.

[0256] 4. Retardant Coating Prepare the non-release coating solution bymixing the Eudragit RS30D, Triethyl Citrate, Talc, and Purified Water.Apply this dispersion over the loaded and overcoated sugar spheres usinga fluid bed coating machine.

[0257] 5. Overcoating Prepare a second overcoating solution bydispersing Opadry White in Purified Water. Apply this dispersion overthe non-release coated denatonium benzoate spheres using a fluid bedcoating machine

[0258] 6. Curing Cure the spheres at 45° C. for approximately 48 hours.

EXAMPLE 6

[0259] In Example 6, a substantially non-releasable form of a bitteringagent (denatonium benzoate) is prepared as denatonium benzoatecontaining granulates. The granulates are comprised of denatoniumbenzoate dispersed in a matrix that renders the denatonium benzoatesubstantially non-releasable. The formulation of Example 6 is listed inTable 6 below. TABLE 6 Amt/unit Ingredient (mg) Denatonium benzoate 0.07Dicalcium Phosphate 53.0 Poly (DI-Lactide-Co- 12.0 Glycolide) polymer(PLGA) MW ˜ 100,000 Ethyl Acetate Total 65.07

[0260] Process:

[0261] 1. Solution Preparation Dissolve PLGA in Ethyl Acetate by mixing.

[0262] 2. Granulation Place the denatonium benzoate, and DicalciumPhosphate in a fluid bed coating machine and granulate by spraying theabove solution.

EXAMPLE7

[0263] In Example 7, a substantially non-releasable form of a bitteringagent (denatonium benzoate) is prepared as denatonium benzoate extrudedpellets. The formulation of Example 7 is listed in Table 7 below. TABLE7 Amt/unit Ingredient (mg) Denatonium benzoate 0.07 Eudragit RSPO 180.0Stearyl Alcohol 55.0 Total 235.07

[0264] Process: 1. Milling Pass stearyl alcohol flakes through an impactmill. 2. Blending Mix Denatonium benzoate, Eudragit, and milled StearylAlcohol in a twin shell blender. 3. Extrusion Continuously feed theblended material into a twin screw extruder and collect the resultantstrands on a conveyor. 4. Cooling Allow the strands to cool on theconveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion.

EXAMPLE 8

[0265] Naltrexone HCl Beads

[0266] In Example 8, Naltrexone HCl beads for incorporation intocapsules were prepared having the following formulation in Table 8below. TABLE 8 Amt/unit Ingredients (mg) Step 1. Drug layeringNaltrexone HCl 2.1 Non-pareil beads (30/35 mesh) 39.98 Opadry Clear 0.4(Hydroxypropymethyl cellulose) Sodium ascorbate 0.027 Ascorbic acid 0.05Step 2. Anionic polymer Eudragit L30D (dry) 2.164 coat Triethyl Citrate0.433 Cabosil 0.108 Step 3. Sustained release Eudragit RS30D (dry)17.475 coat Triethyl citrate 3.495 Cabosil 0.874 Step 4. Seal coatOpadry Clear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total(on dry basis) 69.287

[0267] Process:

[0268] 1. Dissolve naltrexone HCI, ascorbic acid, sodium ascorbate andOpadry Clear in water. Spray the drug solution onto non-pareil beads ina fluid bed coater with Wurster insert.

[0269] 2. Disperse Eudragit L30D, Triethyl citrate, and Cabosil inwater. Spray the dispersion onto the drug-loaded beads in the fluid bedcoater.

[0270] 3. Disperse Eudragit RS30D, triethyl citrate, and Cabosil inwater. Spray the dispersion onto the beads in the fluid bed coater.

[0271] 4. Dissolve Opadry Clear in water. Spray the solution onto thebeads in the fluid bed coater.

[0272] 5. Cure the beads at 60° C. for 24 hours.

EXAMPLE 9

[0273] Naltrexone Multiparticulates

[0274] A naltrexone melt extruded multiparticulate formulation wasprepared. The melt extruded multiparticulate formulation is listed inTable 9 below. TABLE 9 Ingredients Amt/Unit (mg) Naltrexone HCl 2.0Eudragit RSPO 88.0 Stearyl alcohol 15.0 Stearic acid 15.0 BHT 1.0 Total121.0

[0275] Process:

[0276] 1. Blend milled Stearic acid, stearyl alcohol, Naltrexone HCl,BHT, and Eudragit RSPO using a V-blender.

[0277] 2. Extrude the mixture using a Powder Feeder, MeltExtruder(equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer.

[0278] Powder feed rate—4.2 kg/hr; vacuum—˜980 mBar Conveyor—such thatdiameter of extrudate is 1 mm Pelletizer—such that pellets are cut to 1mm in length

[0279] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #16 mesh screen and is retained on the#20 mesh screen.

[0280] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT 114 mg and NMT 126 mg.

EXAMPLE 10

[0281] Naltrexone CR Beads

[0282] A naltrexone sustained release bead formulation was preparedwhich can be incorporated into an opioid controlled release granulationand compressed into tablets. The naltrexone controlled release beadformulation is listed in Table 10 below. TABLE 10 Amt/unit* Ingredients(mg) Step 1. Drug layering Naltrexone HCl 0.609 Non-pareil beads (30/35mesh) 67.264 Opadry Clear 0.547 Step 2. Seal coat Eudragit L 2.545Triethyl citrate 0.636 Glyceryl monostearate 0.239 Step 3. Sustainedrelease Eudragit RS30D (dry) 43.789 coat Triethyl citrate 8.758 Cabosil2.189 Step 4. Seal coat Opadry Clear 2.053 (Hydroxypropylmethylcellulose) Cabosil 1.368 Total 130

[0283] Process:

[0284] 1. Dissolve naltrexone HCl and Opadry (HPMC) in water. Spray thedrug solution onto non-pareil beads in a fluid bed coater with Wursterinsert.

[0285] 2. Disperse Eudragit L, Triethyl citrate, and glycerylmonostearate in water. Spray the dispersion onto the drug-loaded beadsin the fluid bed coater.

[0286] 3. Disperse Eudragit RS, triethyl citrate, and Cabosil in water.Spray the dispersion onto the beads in the fluid bed coater.

[0287] 4. Dissolve Opadry in water. Spray the solution onto the beads inthe fluid bed coater.

[0288] 5. Cure the beads at 60° C. for 24 hours.

EXAMPLE 11 Controlled Release Oxycodone

[0289] In Example 11, a sustained release 20 mg controlled releaseoxycodone formulation was prepared having the formulation listed inTable 11 below. TABLE 11 Ingredients Amt/Unit (mg) Oxycodone HCl 20.0Spray Dried Lactose 59.25 Povidone 5.0 Eudragit RS30D (solids) 10.0Triacetin 2.0 Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25Opadry Pink Y-S-14518A 4.0 Total 129.0

[0290] Process:

[0291] 1. Granulation: Spray the Eudragit/Triacetin dispersion onto theOxycodone HCl, Spray Dried Lactose and Povidone using a fluid bedgranulator.

[0292] 2. Milling: Discharge the granulation and pass through a mill.

[0293] 3. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0294] 4. Milling: Pass the cooled granulation through a mill.

[0295] 5. Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0296] 6. Compression: Compress the granulation into tablets using atablet press.

[0297] 7. Film coating: Apply an aqueous film coat to the tablets.

EXAMPLE 12

[0298] In Example 12, naltrexone beads prepared in accordance withExample 16 are incorporated into the sustained release 20 mg oxycodonetablets prepared in accordance with Example 11 and having the formulalisted in Table 12 below. TABLE 12 Amt/unit* Ingredients (mg) Step 1.Granulation Oxycodone HCl 20.0 Spray Dried Lactose 59.25 Povidone 5.0Eudragit RS30D (dry) 10.0 Triacetin 2.0 Stearyl alcohol 25.0 Talc 2.5Magnesium 1.25 Step 2. Combination OxyContin granulation (Example 125tablet 3) Naltrexone CR beads (Formula 2) 140

[0299] Process:

[0300] 1. Spray the Eudragit/triacetin dispersion onto the OxycodoneHCl, spray dried lactose and povidone using a fluid bed granulator.

[0301] 2. Discharge the granulation and pass through a mill.

[0302] 3. Melt the stearyl alcohol and add to the milled granulationusing a mill. Allow to cool.

[0303] 4. Pass the cooled granulation through a mill.

[0304] 5. Lubricate the granulation with talc and magnesium stearate.Using a mixer.

[0305] 6. Mix naltrexone beads with the above granulation and compressinto tablets.

[0306] Alternate Process:

[0307] 1. Spray the Eudragit/triacetin dispersion onto the OxycodoneHCl, spray dried lactose and povidone using a fluid bed granulator.

[0308] 2. Discharge the granulation and pass through a mill.

[0309] 3. Mix naltrexone beads (example 2) with the above granulation ina Hobar mixer.

[0310] 4. Melt the stearyl alcohol and add to the above mixture. Allowto cool.

[0311] 5. Pass the cooled granulation through a mill.

[0312] 6. Lubricate the granulation with talc and magnesium stearateusing a mixer.

[0313] 7. Compress into tablets.

[0314] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

[0315] One or more aversive agents as described herein can beincorporated into the oxycodone tablets by one skilled in the art. Theone or more aversive agents may be in releasable, non-releasable, orsubstantially non-releasable form or a combination thereof.

EXAMPLE 13

[0316] Controlled Release Hydrocodone

[0317] A sustained release hydrocodone formulation was prepared havingthe formula in Table 13 below. TABLE 13 Ingredients Amt/Unit (mg)Amt/Batch (g) Hydrocodone Bitartrate 15.0 320.0 Eudragit RSPO 76.01520.0 Eudragit RLPO 4.0 80.0 Stearyl Alcohol 25.0 500.0 Total 120.02400.0

[0318] Process:

[0319] 1. Blend milled Stearyl Alcohol, Eudragit RLPO, HydrocodoneBitartrate, and Eudragit RSPO using a Hobart Mixer.

[0320] 2. Extrude the granulation using a Powder Feeder, MeltExtruder(equipped with the 6×1 die head), Conveyor, Lasermike, andPelletizer.

[0321] Powder feed rate—40 g/min; vacuum—˜980 mBar

[0322] Conveyor—such that diameter of extrudate is 1 mm

[0323] Pelletizer—such that pellets are cut to 1 mm in length

[0324] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #16 mesh screen and is retained on the#20 mesh screen.

[0325] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT (not less than) 114 mg and NMT (not more than) 126 mg.

[0326] The sequestered naltrexone formulation of Example 9 can beincorporated in a capsule with the hydrocodone pellets. Preferably, thesequestered naltrexone pellets are indistinguishable from thehydrocodone pellets.

[0327] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

[0328] One or more aversive agents as described herein can beincorporated into a capsule with the hydrocodone pellets, into thehydrocodone pellets, or on the hydrocodone pellets by one skilled in theart. The one or more aversive agents may be in releasable,non-releasable, or substantially non-releasable form or a combinationthereof. Preferably, when pellets comprising the aversive agent(s) areincorporated into the capsule they are indistinguishable from thehydrocodone pellets.

EXAMPLE 14

[0329] Oxycodone HCl Beads

[0330] A sustained release oxycodone HCI bead formulation was preparedhaving the formula in Table 14 below. TABLE 14 Amt/unit* Ingredients(mg) Step 1. Drug layering Oxycodone HCl 10.5 Non-pareil beads (30/35mesh) 45.349 Opadry Clear 2.5 Step 2. Sustained release Eudragit RS30D(dry) 7.206 coat Eudragit RL30D (dry) 0.379 Triethyl citrate 1.517Cabosil 0.379 Step 3. Seal coat Opadry Clear 1.899 (Hydroxypropylmethylcellulose) Cabosil 0.271 Total 70.0

[0331] Process:

[0332] 1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray thedrug solution onto non-pareil beads in a fluid bed coater with Wursterinsert.

[0333] 2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, andCabosil in water. Spray the dispersion onto the beads in the fluid bedcoater.

[0334] 3. Dissolve Opadry in water. Spray the solution onto the beads inthe fluid bed coater.

[0335] 4. Cure the beads at 60° C. for 24 hours.

[0336] The sequestered naltrexone formulation of Example 8 can beincorporated in a capsule with the oxycodone beads. Preferably, thesequestered naltrexone beads are indistinguishable from the oxycodonebeads.

[0337] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

[0338] One or more aversive agents as described herein can beincorporated into a capsule with the oxycodone beads, into the oxycodonebeads, or on the oxycodone beads by one skilled in the art. The one ormore aversive agents may be in releasable, non-releasable, orsubstantially non-releasable form or a combination thereof. Preferably,when beads comprising the aversive agent(s) are incorporated into thecapsule they are indistinguishable from the oxycodone beads.

EXAMPLE 15

[0339] Controlled Release Hydromorphone

[0340] A sustained release hydromorphone HCl formulation was preparedhaving the formula in Table 15 below: TABLE 15 Ingredients Amt/Unit (mg)Hydromorphone HCl 12.0 Eudragit RSPO 76.5 Ethocel 4.5 Stearic acid 27.0Total 120.0

[0341] Process:

[0342] 1. Blend milled Stearic acid, ethocel, Hydrocodone Bitartrate,and Eudragit RSPO using a V-blender.

[0343] 2. Extrude the mixture using a Powder Feeder, MeltExtruder(equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer.

[0344] Powder feed rate—4.2 kg/hr; vacuum—980 mBar

[0345] Conveyor-such that diameter of extrudate is 1 mm

[0346] Pelletizer—such that pellets are cut to 1 mm in length

[0347] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #116 mesh screen and is retained on the#20 mesh screen.

[0348] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT 114 mg and NMT 126 mg.

[0349] The sequestered naltrexone formulation of Example 15 can beincorporated in a capsule with the hydromorphone pellets. Preferably,the sequestered naltrexone pellets are indistinguishable from thehydrocodone pellets.

[0350] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

[0351] One or more aversive agents as described herein can beincorporated into a capsule with the hydromorphone pellets, into thehydromorphone pellets, or on the hydromorphone pellets by one skilled inthe art. The one or more aversive agents may be in releasable,non-releasable, or substantially non-releasable form or a combinationthereof. Preferably, when pellets comprising the aversive agent(s) areincorporated into the capsule they are indistinguishable from thehydromorphone pellets.

EXAMPLE 16 A 20 mg Oxycodone Dosage Form Containing Naloxone as theAntagonist and Multiple Deterring Agents is Prepared

[0352] Various deterring agents used in the previous examples arecombined in one product to produce a tablet which could providetampering resistance to multiple types of abuse by the addicts. A smallamount of naloxone hydrochloride, denatonium benzoate, and xanthan gumare added to an oxycodone formulation during the granulation process.The oxycodone granulation formulation of Example 16 is listed in Table16 below. TABLE 16 Ingredients Amt/Unit (mg) Amount/Batch (gm) OxycodoneHCl 20.0  209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0  50.0Eudragit RS30D (solids) 10.0 100   Triacetin 2.0  20.0 Naloxone HCl 0.61  6.12** Denatonium benzoate 0.07   0.68 Xanthan gum 9.0  90.0 StearylAlcohol 25.0 250.0 Talc 2.5  25.0 Magnesium Stearate 1.25  12.5 OpadryPink Y-S-14518A 5.0  50.0

[0353] Process

[0354] Dispersion: Dissolve naloxone HCl and denatonium benzoate inwater and the solution is added to the Eudragit/Tracetin dispersion.

[0355] Granulation: Spray the Eudragit/Triacetin dispersion onto theOxycodone HCI, Spray Dried Lactose, xanthan gum and Povidone using afluid bed granulator.

[0356] Milling: Discharge the granulation and pass through a mill.

[0357] Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0358] Milling: Pass the cooled granulation through a mill.

[0359] Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0360] Compression: Compress the granulation into tablets using a tabletpress.

EXAMPLES 17-20

[0361] Examples 4-7 can be repeated utilizing a sufficient amount ofcapsaicin in place of, or in addition to the aversive agents disclosedtherein.

[0362] While the invention has been described and illustrated withreference to certain preferred embodiments thereof, those skilled in theart will appreciate that obvious modifications can be made hereinwithout departing from the spirit and scope of the invention. Suchvariations are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. A oral dosage form comprising: a therapeuticallyeffective amount of an opioid analgesic; an opioid antagonist; and abittering agent in an effective amount to impart a bitter taste to anabuser upon administration of said dosage form after tampering.
 2. Theoral dosage form of claim 1, wherein the bittering agent is selectedfrom the group consisting of flavor oils; flavoring aromatics;oleoresins; extracts derived from plants, leaves, flowers, fruitflavors; sucrose derivatives; chlorosucrose derivatives; quininesulphate; denatonium benzoate; and combinations thereof.
 3. The oraldosage form of claim 1, wherein the bittering agent is a flavor oilselected from the group consisting of spearmint oil, peppermint oil,eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds,menthol and combinations thereof.
 4. The oral dosage form of claim 1,wherein the bittering agent is a fruit flavor selected from the groupconsisting of lemon, orange, lime, grapefruit, and mixtures thereof. 5.The oral dosage form of claim 1, wherein the bittering agent isdenatonium benzoate.
 6. The oral dosage form of clam 1, wherein thebittering agent is in a sequestered form.
 7. The oral dosage form ofclaim 1, wherein the antagonist is in a sequestered form.
 8. The oraldosage form of claim 1, wherein the antagonist and the bittering agentare both in sequestered forms.
 9. The oral dosage form of claim 1,wherein said bittering agent is in an amount of less than about 50% byweight of the dosage form.
 10. The oral dosage form of claim 1, whereinsaid bittering agent is in an amount of less than about 10% by weight ofthe dosage form.
 11. The oral dosage form of claim 1, wherein saidbittering agent is in an amount of less than about 5% by weight of thedosage form
 12. The oral dosage form of claim 1, wherein said bitteringagent is in an amount of from about 0.1 to 1.0 percent by weight of thedosage form.
 13. The oral dosage forms of claim 1, further comprising apharmaceutically acceptable excipient.
 14. The oral dosage forms ofclaim 13, wherein said excipient is a sustained release excipient. 15.The oral dosage form of claim 13, said dosage form providing ananalgesic effect for at least about 12 hours after oral administrationto a human patient.
 16. The oral dosage form of claims 1 wherein saidbittering agent is at least partially interdispersed with the opioidanalgesic.
 17. The dosage form of claim 1 having a ratio of opioidantagonist to opioid agonist that is analgesically effective when thecombination is administered orally, but which is aversive in physicallydependent human subjects when administered at the same amount or at ahigher amount than said therapeutically effective amount.
 18. The dosageform of claim 17 wherein said ratio of opioid antagonist to opioidagonist maintains an analgesic effect but does not increase analgesicefficacy of the opioid agonist relative to the same therapeutic amountof opioid analgesic when administered to human patients without saidopioid antagonist.
 19. The oral dosage form of claim 1, wherein theantagonist is in an amount to attenuate a side effect of said opioidagonist selected from the group consisting of anti-analgesia,hyperalgesia, hyperexcitability, physical dependence, tolerance, and acombination of any of the foregoing.
 20. The oral dosage form of claim1, wherein the amount of antagonist released during the dosing intervalenhances the analgesic potency of the opioid agonist.
 21. The oraldosage form of claim 1, wherein the amount of the releasable opioidreceptor antagonist is about 100 to about 1000 fold less than the amountof the opioid agonist.
 22. A method of treating pain comprisingadministering to a patient an oral dosage form of claim
 1. 23. A methodof preparing a pharmaceutical dosage form comprising ombining atherapeutically effective amount of an opioid analgesic; and anantagonist in a dosage form with an effective amount of a bitteringagent to impart a bitter taste to an abuser upon administration of saiddosage form after tampering.
 24. The method of claim 23, wherein saidbittering agent is at least partially interdispersed with the opioidanalgesic.
 25. A method of preventing abuse of an oral dosage form of anopioid analgesic comprising: preparing the dosage form with ananalgesically effective amount of an opioid analgesic; an antagonist;and a bittering agent in an effective amount to impart a bitter taste toan abuser upon administration of said dosage form after tampering.